In June 2011, South Africa signed the United Nations Political Declaration on HIV/AIDS: Intensifying our Efforts to Eliminate HIV/AIDS which explicitly outlined commitment for all UN member states to address the inadequacy of HIV prevention strategies, focusing on men who have sex with men (MSM), injecting drug users (IDU) and sex workers (SW) and to improve access to HIV prevention, treatment, care and support services for migrant populations. This document provides an overview of the situation pertaining to these populations, inclusive of key issues affecting their vulnerability to HIV as identified by the literature and expert opinion, and provides prioritised recommendations for consideration at the next South African National Strategic Plan on HIV/AIDS, TB and STIs (NSP 2012-2016). A thorough data collection and consultation process was undertaken from November 2010-July 2011. This process involved a comprehensive review of published and grey literature, obtained through searches of databases and direct author contact. An extensive network of representatives from research, governmental, civil society and other sectors were engaged during all stages of this project. Stakeholders were contacted electronically, telephonically and in person. Data from the literature was integrated with key informant feedback to develop recommendations targeting key populations in South Africa's HIV response. Additionally, participation by the authors in strategic local and national conferences and workshops enriched the understanding of the contextual factors pertaining to key populations, HIV and South Africa's response.