Mr Manuel was part of a youth movement that attempted to launch a bus boycott across all townships of the Western Cape in 1975; and initiated community newsletter entitled "Kenfacs" in the townships of Ensington /Factreton, the newsletter was used as a basis for community organisation around a series of civic issues in 1979. He was also part of a group who initiated the first community newspaper of scale, Grassroots in 1980.
He was Active in bringing together Parents Supporting Committee which were formed to generate community support for school boycotts. Later he became General Secretary of the Cape Areas Housing Action Committee in 1981 and Regional Secretary and National Executive Member of the United Democratic Front (UDF) in 1983. He was repeatedly detained without trial or placed under house arrest and spending a total of 35 months in detention for these activities between 1985 and 1990.
Mr Manuel was employed by the Mobil Foundation as a Policy Manager on Entrepreneurial and Community Development in 1989 and later he was elected to full-time office in the ANC in August 1991, and appointed as Head of the ANC's Department of Economic Planning being responsible for the shaping of ANC's economic policy during the period 1991 to 1994.
Mr Manuel was appointed to the Advisory Committee of the United Nations (UN) Initiative for Trade Efficiency in August 1994 and as a Minister of Trade and Industry of the Republic of South Africa between 1994 and 1996.
He also served as Governor on the Board of the World Bank, African Development Bank Group and Development Bank of Southern Africa and as Chairman of the Southern African Development Community, Finance and Investment Sector and also as Chairman of the Board of Governors of the International Monetary Fund at Annual meetings in Prague in 2000.
He has served as Special Envoy to the Secretary-General of United Nations (UN) for the Conference on Financing for Development, held in Monterrey, Mexico from 18-20 March 2002, and as a Special Envoy for Development Finance by the United Nations Secretary General Mr. BanKi-moon. He also served as a Commissioner in the Commission for Africa.
He initiated a programme of support for SMME's for South Africa's accession in the Southern African Development Community (SADC) and initiated South Africa's entry into the global economy. He serves on the Commission on Growth and Development as a Commissioner and also Chaired G20 Meetings in November 2007.
Mr Manuel was a Minister of Finance of the Republic of South Africa from 4 April 1996 to 10 May 2009 before being appointed as minister in the Presidency.