Antiretroviral therapy (ART) has fundamentally altered the natural history of HIV/AIDS, sharply reducing HIV-related morbidity and prolonging longevity. However, there seems to be a resurgence in HIV infection rates in some parts of the world that has prompted consideration of pre-exposure prophylaxis (pre-EP) and vaccination. Despite their good viral suppression profiles, most drugs used as part of ART also have unwanted adverse drug reactions/effects (ADRs). In this article we acknowledge the utility of pre-EP in combating HIV transmission, but we also highlight the need to prepare for management of other unexpected outcomes such as ADRs and viral resistance, to ensure the success of the programme.