In the year 2009, Yuji Kaido is an average young adult male diagnosed with a serious disease (the "B-cells") and is put into cryogenic stasis until a cure is found. Twenty-two years later, he is awakened in the midst of a raging battle between armored soldiers and insectoid beings called the "Blue" which have overrun the Earth.
The group of soldiers are from an orbiting space colony collectively called Second Earth and were ordered to recover "sleepers" around the Earth. Among them is the soldier Marlene Angel, who at first appears to be heartless toward others. On the journey to Second Earth, Yuji meets many of the humans that were left behind during the evacuation due to limited resources. Standing orders for Marlene and the other troops are to consider any human survivors on the surface to be already dead, which greatly troubles Yuji.
On their journey all of the soldiers are killed, except for Marlene, causing Yuji to fall into a deep depression as he recognizes the destruction around him and his own inability to save those he cares about. During their travel to Baikonur space base through the mountains, Yuji and Marlene start to develop a bond that softens her sharp edges. Eventually, in Russia, Yuji and Marlene come across another group of soldiers and devise a battle plan to get back to Second Earth. During the operation to escape, Marlene is the last remaining pilot and completely overrun by the Blue. Just when Marlene is about to self-detonate her Armor Shrike, Yuji arrives. Determined not to leave her behind, he comes to her rescue with a team of supporters (service robots). Marlene is overwhelmed at Yuji's efforts to save her. This is a turning point for Marlene and her feelings for Yuji are quite clear for the rest of the series. During the shuttle flight to Second Earth, Marlene and Yuji expose their emotions for each other. Marlene and Yuji's scene is abruptly interrupted as a mutated Blue which hid in the shuttle attacks Yuji, critically injuring him.
Upon arrival, Marlene and Yuji are separated, and Marlene is sent back into training at the education station. Not knowing what happened after he was attacked, Marlene rebels and is bent on finding Yuji. When she does, she finds he has healed and is being trained to use a new specialized "sleeper"-specific Armor Shrike (AS) called the "Double Edge", a battlesuit that is much stronger than the originals used in war against the Blue. It is discovered the illness that Yuji is afflicted with is the key to help destroying the Blue and taking back the planet. He, and other "Sleepers", have "B-cells" which are also the genetic makeup of the Blue.
After intensive training, Yuji and Marlene return to Earth with two other Sleepers named Tony Frost and Alicia Whistle. Tony is an inexperienced AS pilot, but his B-cells are very adept, giving him great AS skills. Alicia is only a young teenager with no combat experience and not much sense of what is going on around her. They and the other forces of Second Earth battle the Blue. They are successful at destroying a few of the largest nests before they head back to Second Earth. However, the battles begin to have a negative effect on Yuji, who has very little regard for human life and is completely obsessed with being better than Tony at killing the Blue. Yuji's actions deeply concern Marlene and she begins to realize something is wrong.
Shortly after returning to Second Earth, the High Council orders the Sleepers on a second offensive against the Blue. Marlene is separated from Yuji once again, but in his current state he does not seem to care. As the Sleepers are carrying out their mission, a battle on Second Earth between two factions is waged. Seno, the head of Second Earth's science division, leads the "Ark" rebellion taking control of the military, lunar resource, and education stations of Second Earth. The High Council escapes to and retains control of the medical station. Marlene learns about the nature of the illness that put Yuji in stasis, the source of his abilities, and the source of the Blue Insectoids. They are a defense mechanism enacted by the Earth to purge the existence of humanity, and the B-cells that exist in the Sleepers could become a potential threat to humanity as well.
After the Ark successfully takes over Second Earth from the ignorant High Council, Marlene heads down to Earth in search of Yuji. When she finds him his B-cells are already beginning to activate, and he begins to go berserk as a killing machine. After struggling and fighting with him, Marlene is finally able to get through to Yuji and helps him overcome his madness by showing her human emotions and feelings for him (this is ironic because in the beginning of the series Marlene is the brutal military soldier and it is Yuji who uses his emotions to help Marlene realize her human sensitivity). Meanwhile, Tony and an unknowing Alicia have also abandoned the remaining ground forces. The troops fend off waves of Blue before escaping with the few remaining survivors. Tony and a now brainwashed Alicia also eventually return to Second Earth, but bring with them several Blue when they board the medical station.
When Yuji and Marlene return to Second Earth, they find that Tony plans to ram the medical station into the military station, which would therefore destroy the heart of Second Earth. He sees this as the "Grand Will of the Earth", in which he will become a "messiah" and cleanse the planet of humanity forever. However, Yuji, Marlene, and a group of other soldiers infiltrate the station, and manage to free Alicia's mind after injuring her. Later, Yuji and Marlene confront and eliminate Tony, while Rick (a close friend and partner to Yuji and Marlene) is slaughtered by a Blue. Alicia ventures back to Tony to die with him as the military destroys the medical station.
After the decision by Seno's junta to abandon Earth, Yuji becomes depressed and contemplates his existence, wondering what he has been fighting for, why he was woken, why he cannot save his friends (Joey near the beginning, Tony from his madness, and Alicia from Tony's brainwashing), and what is truly Earth's will. However, Marlene again is able to get through to Yuji; the two realize they need each other, and finally become lovers.
Yuji decides to return to Earth to once and find out what Earth's will is. After learning from Seno about a new migration pattern of the Blue, Yuji and Marlene take a group of volunteers and head to an area where a massive nest is located. There they find a group of humans surviving in the area. The nest seems impenetrable at first, but they eventually find an entrance with the help of the local people.
The entrance leads to a tunnel where the walls, ceiling, and floor of the cavern are composed of fossil-like Blue. The team finally comes upon a crystal formation in a massive cavern. A huge Blue is birthed from the gel substance sitting atop the formation, and kills everyone except for Yuji and Marlene. Yuji kills it and comes to the conclusion that the sphere will hold the answers he seeks. He sends Marlene, who is pregnant with their child, away to the surface to wait for him. He then gets a vision and can see what the Earth itself can see. Yuji comes to understand how mankind can live alongside the B-cells, and returns to Marlene.
Meanwhile, Second Earth's military station's citizens revolt against Seno. The station's personnel abandon the station for Earth via shuttles. Eventually a firefight erupts over the last remaining overcrowded shuttle, and the station is destroyed by a massive explosion. All around the world from former Blue Nests, long strings of coalescing energy ascend into Earth's atmosphere and form a ring. Marlene and Yuji watch this, realizing Earth is now a safe place to be, and look forward to the rest of their lives together as the sun sets. A final view of the Earth from space is shown with a slightly garbled narration, presumably by the Earth, stating, "Welcome to your next journey".Yuji Kaido (海堂 祐司, Kaidō Yūji) - After being diagnosed with an incurable disease (later discovered to be B-cells), Yuji Kaido decides to be put in cryogenic sleep in hopes that an effective treatment will be developed soon. In 2031, twenty-two years later, Yuji wakes up to find the world overrun by a deadly alien species known as 'Blue'. In 2009 Yuji worked in a gas station, rode his motorcycle, and hung out with his friend Takashi. But in 2031 everything Yuji knew has been destroyed by the Blue. He feels lost and alone in an unforgiving new world. For better or for worse, Yuji is guided by the only thing that he can't trust - his emotions - as he attempts to gain control over his new life. Voiced by: Kenji Nojima (Japanese); Eric Vale (English)
Marlene Angel (マリーン・エンジェル, Marīn Enjeru) - Orphaned at the age of ten because her parents were killed by the Blue, Marlene was one of the few lucky ones to make it to Second Earth. Since then, Marlene has dedicated and trained herself to defeat the Blue. Though seeming very heartless and cold in the earlier episodes, as time progresses, Yuji opens up Marlene's emotions and a bond is created. As Marlene's emotions begin to resurface, everything she was taught to believe in begins to break down. Towards the end of the series, she and Yuji conceive a child together. Voiced by: Houko Kuwashima (Japanese); Laura Bailey (English)
Tony Frost (トニー・フロスト, Tonī Furosuto) - Another sleeper who unlike Yuji, awoke on Second Earth. A very powerful sleeper, He is easily the most advance member of the Sleeper Brigade and trusts no one. Yuji strives to improve himself to be able to beat Tony. Tony seems to have no emotion except for the euphoria of destroying Blue. It becomes apparent in later episodes, however, that he sees himself as a Messiah when his B-cells initiate, and has his own plans for the fate of humanity. Voiced by: Hiroyuki Satō (Japanese); Jerry Jewell (English)
Alicia Whistle (アリシア・ウィッスル, Arisha Wissuru) - Another sleeper on Second Earth who is paired with Tony. She immediately gravitates towards Yuji, seeing Marlene as an obstacle to a relationship with him. She is very young and often naive. Her death is one of the many that troubles Yuji. Voiced by: Miwa Yasuda (Japanese); Lisa Ortiz (English)
Seno Miyagi (セノ・ミヤギ, Seno Miyagi) - A high-ranking member of the science division on Second Earth. He suggests that Marlene and Yuji are kept together in order to get the best results from Yuji in the sleeper program. Not agreeing with the High Council's leadership of Second Earth or its reckless use of the sleepers, he eventually forms a group called The Ark, which would later overthrow the High Council's "government" on Second Earth. Seno would subsequently become the leader of Second Earth, but only for a brief time. His order to abandon Earth eventually results in a revolt and his execution by citizens whom wanted to return to Earth. Voiced by: Katsunosuke Hori (Japanese); Kyle Hebert (English)
Rick - Rick is a military Elite, and although he fights on the Sleeper Brigade, he is not a Sleeper. He is cocky, confident, and loves strong women, especially Marlene. Voiced by: Eiji Ito (Japanese); Sean Schemmel (English)
Doug Vreiss - Doug is the assistant to the High Council and a high-ranking official on Second Earth. He is the Director of the Military Station, and also participates in High Council inquireies. He is later shot and killed by Miyagi. Voiced by: Shunsuke Shima (Japanese); Bradford Jackson (English)