Surveillance data on high school adolescent sexual activity, including teenaged pregnancy rates and incidence of sexually transmitted infections (STIs), require pediatricians and other youth providers to be competent and confident in addressing sexual and reproductive health care needs in adolescent and/or young adult populations. The American Academy of Pediatrics has published guidelines, recommendations, clinical reports, and resources on the promotion of healthy sexual development in clinical settings, encouraging sexual health assessments that are inclusive of HIV and STI testing as an integral component of comprehensive health visits. The need for a more determined effort to address sexual health as it relates to HIV specifically is evidenced by a decrease in the number of in-school youth reporting ever being tested, 15- to 24-year-olds representing 21% of new infections, and estimates that >40% of youth with HIV are undiagnosed. Ending the HIV epidemic requires adherence to published HIV testing recommendations, sexual health assessments, screening for STIs, and appropriate primary and secondary prevention education. Preexposure prophylaxis, an efficacious biomedical prevention intervention for reducing HIV acquisition, was approved in July 2012 and in May 2018 was authorized for use in minors. This state-of-the-art review article provides background information on preexposure prophylaxis, current guidelines and recommendations for use, and strategies to introduce and implement this valuable HIV prevention method in clinical practice with adolescents and young adults.Copyright © 2020 by the American Academy of Pediatrics.