While international standards are important for conducting clinical research, they may require interpretation in particular contexts. Standard of care in HIV prevention research is now complicated, given that there are now two new biomedical prevention interventions – ‘treatment-as-prevention’, and pre-exposure prophylaxis – in addition to barrier protection, counselling, male circumcision and treatment of sexually transmissible infections. Proper standards of care must be considered with regard to both normative guidance and the circumstances of the particular stakeholders – the community, trial population, researchers and sponsors. In addition, the special circumstances of the lives of participants need to be acknowledged in designing trial protocols and study procedures. When researchers are faced with the dilemma of interpretation of international ethics guidelines and the realities of the daily lives of persons and their practices, the decisions of the local ethics committee become crucial. The challenge then becomes how familiar ethics committee members in these local settings are with these guidelines, and how their interpretation and use in the local context ensures the respect for persons and communities. It also includes justice and the fair selection of study participants without compromising data quality, and ensuring that the risks for study participants and their community do not outweigh the potential benefits.