In 2007 Mollema won the prestigious stage race for upcoming talents Tour de l'Avenir and the Circuito Montañés.
He joined the Rabobank ProTeam in 2008, signing his first contract as a professional. His first notable result was a 6th position in the final classification of the 2008 Vuelta a Castilla y León. He made his ProTour debut in the Tour de Romandie, but did not finish the race due to a fall, which resulted in a fractured collarbone. He fully returned in top shape in the Deutschland Tour, in which he started as Rabobank's team leader, eventually finishing 7th in the overall general classification. After a disappointing spring in 2009, the season was over for Mollema due to infectious mononucleosis (Pfeiffer's disease).
Mollema made his Grand Tour debut in the Giro d'Italia in which he made a good impression but fell short of a top 10 classification and winning the young rider competition, partially due to missing out on a break-away of 50 riders in which a lot of direct opponents gained a 12 minutes lead. Mollema continued to ride strong later in the season with a mountain stage win in the Tour de Pologne and a third place overall after winner Dan Martin and runner-up Grega Bole.
In the spring of 2011 he already showed good form with a ninth place overall in Paris–Nice and tenth overall in the Volta a Catalunya. He eventually did not show his good form in the Ardennes classics and rode disappointing results. The main objective of Mollema's 2011 season was his first ever Tour de France. As preparation for the Tour he rode, together with teammate Steven Kruijswijk, the Tour de Suisse. Both riders performed extremely well in a strong field. This resulted for Kruijswijk in a podium finish but Mollema fell short for the podium due to a flat tyre. Due to illness his general classification performance in the Tour de France was not a success. In the last week he stated that he felt better and tried for a break-away. This resulted in a second place in the 17th stage after Edvald Boasson Hagen of Team Sky.
Mollema returned to action in his third Grand Tour, the Vuelta a España. On the steep uphill finishes in stage 5 and 8 he finished in the top five. He did not lose any crucial time in the first week and was awarded the red leader's jersey after his second place in stage 9. Due to his weaker time trial skills compared to other general classification contenders such as Bradley Wiggins, Chris Froome and Vincenzo Nibali, he lost the leader's jersey a day after he had won it. Mollema rode well after the time trial and was heading for a podium position, but he fell to fourth place overall due to the performance of Juan José Cobo on the Alto de l'Angliru. Mollema eventually came onto the podium in Madrid as winner of the points classification. It was the first time since 1992 that a Dutchman won a major classification in a Grand Tour, after Eddy Bouwmans won the young rider classification in the Tour de France.
In 2013, Mollema carried some good form finishing 2nd in the Vuelta a Murcia, 3rd in the Vuelta a Andalucía, and 4th in the Criterium International. In the Tour de Suisse, Mollema won stage 2 marking his first victory in 2013. After having a strong ride in the mountains, Mollema entered the final time trial in 4th position. He later moved up into 2nd that day. Mollema's good form continued at the Tour de France, where he finished fourth on the first mountain stage to Ax 3 Domaines to rise to fourth in the general classification. He finished eighth on the next stage and rose to third overall after Richie Porte lost more than 18 minutes. On stage 13 he rose to second in general classification when Alejandro Valverde lost almost 10 minutes after suffering a puncture with approximately 80 kilometres (50 miles) left, while also gaining over a minute on Froome's lead. However, he lost time in the last week due to illness and finished 6th in the general classification. Mollema also rode the Vuelta a España. He won Stage 17 of the race by attacking from the peloton 500 metres from the line, and holding off the chasing pack led home by Edvald Boasson Hagen (Team Sky).
At the Tour de France, Mollema sat seventh overall heading into the penultimate stage, an individual time trial 54 kilometres (34 miles) in length. However, riding a new Bianchi for the first time, Mollema could only place in 140th position and slipped to tenth overall in the general classification, 21 minutes and 24 seconds behind the winner, Vincenzo Nibali.
At the end of the 2014 season, Mollema left Belkin Pro Cycling to join Trek Factory Racing.
In March 2015, Mollema finished second overall behind Nairo Quintana (Movistar Team) at Tirreno–Adriatico. However, he subsequently suffered a back injury which affected his Tour de France preparations. Mollema went on to finish seventh overall in the Tour.
In September 2015, Mollema won the Tour of Alberta stage race in Canada.
On Stage 12 of the Tour de France, Mollema bridged across to an attack by race leader Chris Froome (Team Sky) and Richie Porte (BMC Racing Team) on Mont Ventoux, and was the only general classification contender able to do so. However, all 3 riders were involved in a crash with a motorbike after spectators on the road forced the motorbike to stop. Mollema was able to remount his bike and continued riding, while Porte was delayed and passed by the other general classification contenders and Froome ditched his bike and continued on foot until receiving a replacement bike from his team car. Mollema finished the stage 1 minute and 40 seconds ahead of Froome, and the initial standings placed Mollema in second overall behind new leader Adam Yates (Orica–BikeExchange). However, Froome was awarded the same time as Mollema after a jury decision, and retained the yellow jersey. The revised standings also placed Nairo Quintana ahead of Mollema, who was now fourth overall. Mollema criticised the UCI's handling of the stage afterwards. On Stage 13, Mollema produced what he described as "the best time trial of my life" to place sixth on the hilly route over 37.5 kilometres (23.3 miles). He finished 51 seconds down on Froome, but took time out of all the other general classification contenders and rose to second overall. He ultimately fell to eleventh overall by the end of the race.