Clinical trials of HIV pre-exposure prophylaxis (PrEP) antiretroviral drugs have shown excellent protection against HIV acquisition when plasma drug levels are detectable, indicating good adherence. Cost-effectiveness depends on epidemic context, adherence, drug cost, and other factors. For individuals at highest risk of HIV who are unable to use proven HIV prevention methods such as condoms and sterile injecting equipment, PrEP may be a workable option over short- to medium-term risky periods of their lives. Adding PrEP to HIV prevention programmes will be most effective as part of a combination prevention strategy that addresses both immediate risks and underlying vulnerabilities, and the pathways that link them. Determining who is most motivated to adhere to PrEP and supporting them through participant-centred approaches that assist people to find their own adherence solutions will be critical to determining the real-life cost-effectiveness of PrEP for HIV prevention and for whom HIV PrEP is most suited.