Prior to his first appointment as Minister of Health of the Republic of South Africa, Dr Motsoaledi had served as Chairperson of the Sekhukhune Advice Office from 1986 to 1994; as Chairperson of Hlahlolanang Health and Nutrition Education Project in 1989; as a Deputy Chairperson of the African National Congress (ANC) in the then Northern Transvaal from 1991 to 1992; as Head of the ANC Elections Commission for Limpopo in 1994; as Head of the ANC Economic and Infrastructure Desk and as Head of the ANC Research and Briefing of election Task Team in Limpopo in 1994. Dr Motsoaledi has also served as a member of the Limpopo Provincial Legislature from 1994 to 2009; as a member of the Limpopo Provincial Executive Council (MEC) for Education from 1994 to 1997; MEC for Transport from 1998 to 1999 and MEC for Agriculture, Land and Environment in 1999.

Member of Provincial Executive Committee of ANC in Limpopo Province 1991-2001, Before unbanning of ANC in 1990 served in leadership positions in various mass democratic movement structures including in the NEC of the United Democratic Front MEC Education, Sports and Culture in Limpopo Province 1997-2000.

First MEC for Health and Social Development in Limpopo Province from 1994-1997, Qualified as a Medical Practitioner MBChB 1983 University of Natal and practised in various hospitals in KZN, Gauteng, Mpumalanga and Limpopo till April 1994.