Shouldering two-thirds of the global HIV/AIDS prevalence of 34 million, sub-Saharan Africa has been the “ground zero” for intense research scrutiny and interventional programming over the last three decades. This programming landscape cannot be characterized without the role of civil society organizations (CSOs), which include a broad spectrum of nongovernmental organizations (NGOs), faith-based organizations, and community-based organizations (CBOs). In a context of crises in the sociopolitical economy and deteriorating health indicators in the early 1990s, the rapid growth of CSOs filling in the expanding spaces coincided with the emergence and eventual explosion of HIV/AIDS, subsequently bringing about the rise of AIDS NGOs. The NGOization of HIV/AIDS services would develop not only organically—driven by HIV activists at the grassroots—to fill gaps where governments lacked in response, but also as they were spurred on by large external official and philanthropic donor funds. Throughout Africa, these groups have been responsible for transferring significant proportions of the now about US $10 billion annual global spending to needy persons affected by HIV/AIDS, and have played a leading role in developing and implementing policies, strategies, and programs to mitigate the impact of and to prevent and treat the disease. The response by CSOs has followed the historiography, geography, and patterns of spread often utilizing approaches based in solid scientific evidence but also as dictated by the funders. Despite challenges and criticisms, this effort has helped reduce HIV incidence by 25 % in 22 African countries during 1990–2009 and expand treatment access from just 50,000 persons in 2002 to over 5 million in 2011.