With the struggle against apartheid achieved, South Africa faced the new struggle of overcoming the HIV/AIDS pandemic. This paper examines the response of government, the innovation system and civil society in rising to the challenge. The response included a fatal denialism concerning the etiology of AIDS, a fatalism that constitutes political market failure. This political market failure was counteracted through the emergence of social entrepreneurship in the form of the Treatment Action Campaign (TAC) that mobilized civil society and like-minded health practitioners and researchers within the innovation system. Dependency Theory coupled with a Quadruple Helix model of the innovation system offer possible explanations of this complex human tragedy and the way that government was compelled to embark on a massive program of providing anti-retroviral therapy that has now significantly improved life expectancy. The paper provides socio-economic context, appraisal of the innovation system, and a sketch of how the Quadruple Helix took form. Of special importance is the independence of South Africa’s ‘Republic of Science.’ Independent courts were critical in allowing TAC to obtain remedy against government, Big Pharma, and AIDS dissident scientists. It is argued that its Republic of Science met its obligation of objectivity by shifting emphasis to the cause of AIDS research in the face of official denialism. In effect, the system of innovation and social entrepreneurs are shown to have acted in concert in constituting a Quadruple Helix.