Members of an HIV-prevention research network were asked to describe ethical challenges faced in their work. Major themes included acceptable standards of care for participants, defining research of relevance to host countries, reducing risks related to stigma, designing research that meets local needs without contributing to an inadequate status quo, and ensuring informed consent for complex research with potentially vulnerable participants. The challenges are interrelated and highlight the need for innovative, practical strategies to be incorporated into the planning, design, and conduct of HIV prevention trials. Research in applied ethics to support decision-making about HIV prevention research is needed, along with ethics training, mechanisms to support community-wide benefit from research, and expanded dialog on ethics surrounding HIV prevention and public health research.