Molefe was born in 1952 in Sophiatown, Johannesburg. He was one of eight children, and spent most of his youth living with his aunt. His mother was a domestic worker and his father a labourer, and he grew up poor. Molefe is married to Boitumelo Elizabeth Plaatjie and has four children. He is a Christian, and has always been involved in religious organisations.
When growing up, Molefe used to visit his mother in the white suburb where she worked, and remembers being harassed by the white children in the area. He also has memories of police brutality in the townships, where he witnessed pass and liquor raids. Molefe became politically aware from a young age as a result of his experiences. He saw the need for change in South Africa, and joined the Black People’s Convention (BPC) in 1973 while still at school. The next year he joined the South African Students’ Movement (SASM), and in 1976 was involved in the Soweto Uprising.
Molefe was a founding member of the Azanian People’s Organisation (AZAPO), which was founded by the Soweto Action Committee in 1978. During 1979 and 1980 Molefe was chairperson of the Soweto branch of AZAPO. He came under the influence of Joe Gqabi, Nelson Mandela and others, and began to realise the need to involve people of other colour in the struggle against apartheid. He started thinking about working together with people from other movements, but AZAPO, within the ideology of Black Consciousness, was not the type of movement for this development. He resigned from it in 1981.
Molefe became involved in the establishment of the Soweto Civic Organisation, and served on its Committee of Ten between 1982 and 1984. In 1983 Molefe participated in the formation of the United Democratic Front (UDF). He was elected Secretary for the Transvaal region, and later served as national secretary. He was involved in the UDF throughout its existence, and played an important role in the Front, aside from when he was in prison.
Molefe was detained numerous times during his life. The first time was in August 1976, for seven months. He was arrested again in both 1981 and 1984. In 1985 Molefe was arrested for terrorism, high treason, subversion, murder and participation in a banned organisation. He was tried together with 21 other activists in the drawn out Delmas Trial. The trial continued for 3 ½ years, and bail was denied for the duration. Molefe was handed down a ten-year jail sentence, but the Supreme Court overturned it in 1989.
In 1990 Molefe became involved with the African National Congress (ANC) directly, which had just been unbanned. In the same year he was elected chairperson of the ANC’s Alexandra branch and deputy chairperson of the ANC’s PWV region. In 1991 Molefe was elected to the NEC of the ANC and to the National Working Committee of the ANC, positions he still holds. He became involved with rebuilding the ANC, was appointed chairperson of the 80th Anniversary Celebration Committee of the ANC and in 1992 became chairperson of the national elections commission of the ANC. In 1994 Molefe was made Premier of the North-West Province, a position he held until April 2004.