Raised in Soweto in the former Transvaal after his family was forcibly removed from Alexandra, Motlanthe was recruited into uMkhonto weSizwe, the armed wing of the African National Congress (ANC), after he finished high school.

However, on his first day in office, he replaced Health Minister Manto Tshabalala-Msimang with Barbara Hogan, effecting a break with Mbeki's HIV/AIDS policy, which had been criticised as ineffective and driven by denialism.

[8][10]: 5–6  His father, Louis Mathakoe Motlanthe (d. 1989),[11] worked as a cleaner at St John's College and later for Anglo American, and his mother, Masefako Sophia Madingoane (d. 2014),[12] was a domestic worker and then a machinist in a clothing factory.

[10]: 8  In 1964, the Anglican church awarded him a bursary to study in Swaziland, but the Bantu Affairs Department of the apartheid government denied him permission to leave the country.

[14][10] After Matric (which in South Africa means completing final year of high school), Motlanthe got a job, which he held until his arrest, supervising township liquor stores in the commercial unit of the Johannesburg City Council.

[9] He was found guilty under the Terrorism Act on charges relating to his MK activities – specifically, for having been trained to commit sabotage, for having received explosives for that purpose, and for promoting the ANC[13] – and was sentenced to prison.

In June 1987, shortly after his release from prison, Motlanthe became an education officer at the influential National Union of Mineworkers (NUM), which was then led by Cyril Ramaphosa.

[24]: 250–251 In October 2004, in a speech to the Black Management Forum, Motlanthe delivered what was perceived as "an attack" on BEE, a cornerstone of the ANC's economic and transformation policy.

"[30] His rationale was that the narrow base of BEE beneficiaries limited the success of the current policy, which he said had been characterised by transfer of wealth instead of genuine economic transformation.

The emails ostensibly showed a group of ANC politicians and government officials discussing how to discredit Zuma, who was Mbeki's major political rival, and Motlanthe himself.

'"[23] [T]he question that we must answer is where is the ANC?… When elected leaders at the highest level openly engage in factionalist activity, where is the movement that aims to unite the people of South Africa for the complete liberation of the country from all forms of discrimination and national oppression?

[41] His last act as secretary general was to deliver a memorable organisational report to the conference, criticising various wings of the party and especially the outgoing National Executive Committee, which he said had failed to resolve problems relating to factionalism and branch-level fraud.

"[50] On the other hand, local journalist Ranjeni Munusamy claims that Motlanthe did not take a clear position in favour of either candidate until the conference itself,[51] and that, as secretary general, he was focused on "trying to hold things together" and "had to rise above the camp warfare.

"[52] He was certainly involved in attempting to maintain discipline during the conference – on the first day, he confiscated partisan placards from some delegates and took the stage to restore order when the session devolved into shouting from Zuma supporters.

On 22 September, while the resignation was still being formalised, Zuma said that the ANC would not confirm its choice until after the vote, but hinted to the press that it was Motlanthe, saying, "I am convinced, if given that responsibility, he would be equal to the task.

Backbenchers at the parliamentary session which elected Motlanthe sang pro-Zuma songs,[67] but it was reported that his appointment had broad support within the ANC and in the business community,[68] and even among opposition parties.

In the opinion of commentators, the most significant change made by Motlanthe to Mbeki's cabinet in September 2008 was the removal of Manto Tshabalala-Msimang from the health ministry.

[69][71] Tshabalala-Msimang's HIV/AIDS policy, especially her advocacy of herbal remedies, had been highly controversial and widely condemned, and Motlanthe replaced her with Barbara Hogan, who said in November, "The era of denialism is over completely in South Africa.

[81][82] Ahead of the 2005 Zimbabwean parliamentary election, Motlanthe had delivered what was considered the ANC's "first public criticism" of Robert Mugabe's ZANU-PF regime in Zimbabwe.

[23] Once inaugurated as president, Motlanthe asked Mbeki to remain in his role as mediator between ZANU-PF and Morgan Tsvangirai's Movement for Democratic Change,[86] and his government "[threw] its weight behind" the resulting Zimbabwean power-sharing agreement.

"[33]In December 2008, when new allegations emerged of corruption in the 1999 Arms Deal, Archbishop Desmond Tutu and former state president F. W. de Klerk wrote to Motlanthe requesting he establish an independent commission of inquiry.

[123]While president, Motlanthe had been praised for sending the Film and Publications Amendment Bill – which included pre-publication censorship provisions – back to Parliament, citing concerns about its constitutionality.

[177] During his last parliamentary session, he received a standing ovation from other MPs, and Mlangeni told Motlanthe and the rest of the National Assembly that Walter Sisulu had "always wanted" him to become president.

[182]In an interview in March 2016, though not directly using Zuma's name, Motlanthe spoke of an "integrity gap" in the ANC and criticised leaders who failed to take accountability and resign from office when warranted.

[191][192] In April 2021, the ANC's National Working Committee asked him to oversee talks between competing factions in the party's highly divided Free State branch.

[198] Later that year, Zimbabwean President Emmerson Mnangagwa appointed him chairperson of a commission of inquiry into post-election unrest in Harare, during which state forces had killed several civilians.

[201] In 2020, he and former Nigerian president Olusegun Obasanjo co-authored an article in which they disowned their administrations' drug policies, arguing that criminalisation and prohibition were irrational and ineffective, and declaring, "We were wrong.

[51] He is also known for his restrained, measured demeanour,[167][225][51] although his friends inside the ANC report that "he can be a great joker" and that he frequently defused bad moods among his Robben Island cohorts.

"[132] English diplomat and politician Robin Renwick said in 2012 that, after Mandela, Motlanthe was South Africa's most highly respected leader overseas, "seen to embody the best virtues of the old guard of the ANC.

"[10]: 328  Motlanthe is viewed as having assumed an "elder statesman" role after his retirement,[172] with the Sunday Times commenting in 2018 that he was the first of South Africa's former presidents to have found "the right role" in public life, in his case as "a reluctant president, a caretaker who stepped in to steady the ship and gracefully retreated to a lesser position, a custodian of democratic values and elder statesman.