Post-exposure prophylaxis (PEP) to prevent HIV acquisition has been recommended for over three decades, but remains underutilised. Over the past decade, clinical trials have established the safety and tolerability of newer PEP regimens, particularly those containing integrase strand transfer inhibitors (INSTIs) combined with a tenofovir and lamivudine or emtricitabine backbone. Several of these regimens were better tolerated than historical controls. Studies in macaques found that shorter courses of PEP with INSTIs were effective, particularly if dosing occurred close to the time of retroviral exposure.