Biomedical research is critical to identifying effective and safe interventions, such as vaccines, microbicides, male circumcision and antiretrovirals, for prevention. Funding for clinical prevention trials is highly competitive and the benchmarks of success ultimately reduce to quickly enrolling a select group of people at risk, keeping them enrolled, and inducing them to be compliant with trial requirements - all at the lowest cost possible. Juxtaposed with this reality is the fact that HIV is situated with poverty, exploitation, assaults on human dignity, and human rights abuses. The result is a complex web of ethical challenges that are socially constructed along lines of wealth and power. While social science research methods are commonly employed to examine such topics, they have played a marginal role in biomedical HIV prevention research. Why? To answer this question, a core set of persistent interlocking social, behavioural and ethical challenges to biomedical HIV prevention research are described. A critique is offered on how the social has been framed relative to the behavioural, ethical and biomedical components. Examples of how this framing has devalued social knowledge are provided, including the conflation of qualitative research with anecdotal reporting, a bias toward brevity and accuracy over external validity, and difficulties in distinguishing between a moral understanding of social norms and achieving a moral outcome when confronted with ethical challenges in research. Lastly, opportunities are identified for enhancing the success of biomedical HIV prevention research through development of a coherent programme of social science research. Recommendations are offered for reframing the social as a valid domain of scientific inquiry in this highly applied and interdisciplinary context.