On 30 July 2009, he became Acting President after the retirement of President Josefa Iloilo. On 5 November 2009, he was sworn in as President of Fiji. George Konrote was elected to succeed him in October 2015.
Born to a family of politically powerful chieftains, Nailatikau's career spanned 20 years in the military and 17 years in the diplomatic service. Following his education at Bau District School, Draiba Fijian School, Levuka Public School and Queen Victoria School, Nailatikau trained as a soldier in New Zealand. In 1966, he served on secondment in the 1st Battalion, Royal New Zealand Infantry Regiment and was posted to Sarawak, Malaysia, during Indonesia's "Konfrontasi" against Malaysia. He proved to be a popular and highly respected officer. When he returned to the Fiji Infantry Regiment, he rose steadily through the ranks. By 1987, he held the rank of Brigadier-General, and was the Commander of the Royal Fiji Military Forces. While visiting Australia, he was deposed from this position, however, when the third-ranked officer, Lieutenant-Colonel Sitiveni Rabuka staged the first of two coups and seized power.
Nailatikau retired from the Army and decided to pursue a new career in the diplomatic service. After completing the Foreign Service Course at Oxford University in the United Kingdom, he was appointed High Commissioner to the United Kingdom and accredited as Fiji's Ambassador to Denmark, Egypt, Germany, Israel and the Holy See. He was later appointed as Fiji's Roving Ambassador and High Commissioner to the member states of the South Pacific Forum, before taking up a post as Permanent Secretary for Foreign Affairs and External Trade in 1999.
In the aftermath of the failure of the Fiji coup of 2000, a coup which Nailatikau strongly opposed, he was nominated for the position of Prime Minister, to help rebuild Fiji's shattered institutions. He withdrew his nomination, however, in favour of Laisenia Qarase, who was considered more of a consensus candidate, but became Deputy Prime Minister and Minister for Fijian Affairs in the interim Cabinet. In 2001, after democracy had been restored in a general election, he defeated, by a vote of 41 to 29, Joeli Kalou for the position of Speaker of the House of Representatives, a position he held until after the 2006 elections.
Following the coup d'état of 5 December 2006, he was sworn in as Minister for Foreign Affairs and External Trade in the new interim government of Prime Minister Commodore Frank Bainimarama on 8 January 2007.
He was nominated to become the new vice-president by the Fiji president Ratu Josefa Iloilo on 10 April 2007, but was rejected by the GCC. On 17 April 2009, after Fiji experienced a constitutional crisis, Ratu Epeli was appointed Vice President.
Nailatikau served as interim Minister of Foreign Affairs, International Co-operation and Civil Aviation under Prime Minister Frank Bainimarama, beginning in January 2007. On 23 September 2008, Bainimarama said that Nailatikau would be moved to the post of Minister for Provincial Development and Multi-Ethnic Affairs on 5 October 2008, while Bainimarama would take over his previous duties. According to Bainimarama, he "decided to give him this new responsibility given his extensive knowledge and hands-on experience on the workings of the Civil Service, Governments role in rural development and the sources of assistances available to facilitate such development", while also stating that Nailatikau had "excellent public relations appeal, which is very much needed in outreaching and inter-facing with rural people."
On 25 September 2007, Ratu Epeli was appointed as acting Prime Minister while interim Prime Minister, Voreqe (Frank) Bainimarama, was away in New York for the week.
On 30 July 2009, he became Acting President after the retirement of 88-year-old President Iloilo. The President was supposed to be appointed by the Great Council of Chiefs (effectively abolished by the military-backed regime) under the 1997 constitution that Iloilo had abrogated, but Bainimarama announced that a new President would be appointed by his Cabinet at the regime's convenience. Nailatikau was formally appointed to the office on 5 November 2009.
On 14 June 2005, Nailatikau was appointed the UNAIDS Special Representative for the Pacific. According to the Joint United Nations Program on HIV/AIDS, he was chosen because his political position, his respect throughout the Pacific region, and his outspokenness on AIDS-related issues. He had previously served as a UNAIDS Pacific spokesman, and in October2004 chaired the first conference of Pacific Parliamentarians on the Role of Pacific Parliamentarians in the fight against HIV/AIDS, in Suva.
Nailatikau's outspoken calls to tackle the AIDS crisis have attracted controversy. On 22 November 2005, he called on people to recognize the reality that promiscuity existed, and that safe sex needed to be promoted to combat the associated AIDS risk. It was unrealistic to deny promiscuity and just promote abstinence, he considered, adding that this was a matter of life and death. He also called on churches to face the reality that promiscuity existed among their own congregations, and to meet the problem "head on" and play a part in promoting the use of condoms.
He represented the Commonwealth Parliamentary Association (CPA) at the World AIDS Conference in Toronto in August 2006.
As a chief by birth through his paternal side via his maternal grandmother who is the granddaughter of Ratu Seru Cakobau, Epeli Nailatikau has the title of Ratu. He is the second son of Ratu Edward Cakobau, who commanded the Fijian Battalion in World War II. He is also a great-great-grandson of Seru Epenisa Cakobau from his granddaughter Adi Litia Cakobau, the first monarch to rule over a unified Fijian kingdom after conquering all the tribes of Fiji and uniting them under his leadership, and who ceded the Fiji Islands to the United Kingdom in 1874. In addition, he is a grandson of King George Tupou II of Tonga. His father is the product of issue between HM King George Tupou II and Adi Litia Cakobau who was sent to Tonga as a trial bride to the King but was later rejected as they could not wed under the normal Tongan constitution.
In 1981, he married Adi Koila Mara, the second daughter of modern Fiji's former Prime Minister and President Ratu Sir Kamisese Mara. Adi Koila has also been a politician in her own right; like her husband, she served as a Member of Parliament, Cabinet minister, and Senator. They have two children: a son, Kamisese Vuna (named after Adi Koila's father), and a daughter, Litia Cakobau.