In 2023, an estimated 1.3 million new HIV infections occurred globally (Global HIV & AIDS statistics Fact Sheet 2024, UNAIDS. . Accessed 10 July 2024). The overall incidence has declined substantially since the peak of new infections reached 3.3 million in 1995. While failing to meet a goal of no more than 370,000 annual new infections per year by 2025, great strides have been made through gradual, systemic implementation of mitigating interventions. One of those mitigating practices is the administration of Post-Exposure Prophylaxis (PEP) to persons who have been exposed to, or possibly exposed to, HIV. Conceptually, Occupational Post-Exposure Prophylaxis (OPEP) developed first. OPEP emerged as a prevention measure for health care workers at risk of having been exposed to HIV through a needle stick injury or related exposure in the workplace. After the strategy was found to be successful in lowering the risk of HIV transmission to health care workers in an occupational setting, the concept and practice was expanded to high-risk exposure events beyond the health care setting. When used in this context, the practice is referred to as Nonoccupational Post-Exposure Prophylaxis (NPEP). The related strategy and success in preventing vertical transmission of HIV from mother to child using antiretroviral medications during pregnancy, labor, delivery, and postnatally in the newborn offered proof of concept that Pre-Exposure Prophylaxis (PrEP) could be expanded to other high-risk circumstances. PrEP, a medication administered to persons with known risk factors for contracting HIV, has emerged as a standard of care for reducing HIV transmission. This chapter summarizes the history and reviews the recommended management plans for patients for whom PEP and PrEP are administered.