Adolescents in the United States are at increased risk for acquiring HIV and other sexually transmitted infections (STIs). Rates of chlamydia, gonorrhea, and primary and secondary syphilis are increasing among individuals aged 15 to 24 years, among both sexes. Approximately 1 in 5 new HIV diagnoses is occurring among individuals aged 13 to 24 years. Compared with heterosexual and cisgender youth, sexual and gender minority youth may be more likely to have had sex before age 13 years, and young transgender women have the highest rates of HIV and STIs than other sexual and gender minority youth. Comprehensive, culturally sensitive, and developmentally sensitive care is needed to address sexuality-related issues in adolescents and young adults. This article summarizes a presentation by Allison Agwu, MD, ScM, at the International Antiviral Society-USA (IAS-USA) annual continuing education program held in New York, New York, in September 2019.