Improvements in biomedical technologies, combined with changing social attitudes to sexual minorities, provide new opportunities for HIV prevention among gay and other men who have sex with men (GMSM). The potential of these new biomedical technologies (biotechnologies) to reduce HIV transmission and the impact of HIV among GMSM will depend, in part, on the degree to which they challenge prejudicial attitudes, practices and stigma directed against gay men and people living with HIV (PLHIV). At the structural level, stigma regarding gay men and HIV can influence the scale-up of new biotechnologies and negatively affect GMSM’s access to and use of these technologies. At the personal level, stigma can affect individual gay men’s sense of value and confidence as they negotiate serodiscordant relationships or access services. This paper argues that maximising the benefits of new biomedical technologies depends on reducing stigma directed at sexual minorities and people living with HIV and promoting positive social changes towards and within GMSM communities. HIV research, policy and programs will need to invest in: (1) responding to structural and institutional stigma; (2) health promotion and health services that recognise and work to address the impact of stigma on GMSM’s incorporation of new HIV prevention biotechnologies; (3) enhanced mobilisation and participation of GMSM and PLHIV in new approaches to HIV prevention; and (4) expanded approaches to research and evaluation in stigma reduction and its relationship with HIV prevention. The HIV response must become bolder in resourcing, designing and evaluating programs that interact with and influence stigma at multiple levels, including structural-level stigma.