After more than twenty years of programming and activism aimed at stemming the sexual transmission of HIV (and addressing the needs of those most vulnerable to infection) the HIV/AIDS epidemic continues to grow worldwide. Taking up this concern, this paper argues that one of the reasons why HIV prevention has had limited success is because of inadequate conceptualization of human sexuality in such work. Giving sexuality a more prominent position in responses to the epidemic raises a range of issues, including theorization of gender, understanding of sexual subjectivity, the significance of pleasure (or lack of pleasure) in sexual decision-making, and conceptualization of sexual behaviour and culture. Taking these themes forward entails asking significant questions about the underlying paradigmatic and methodological commitments of mainstream HIV/AIDS research, especially the tendency to reproduce accounts of human sexuality as if it were a measurable form of conduct only. Advocating new approaches that take the meaning and symbolic value of sexualities into account complicates established orthodoxies in the field whilst offering potential for more effective HIV prevention strategies.