Substance abuse, specifically the use of illicit drugs that are administered intravenously, continues to play a role in the transmission of human immunodeficiency virus type 1 (HIV-1) among adolescents and young adults (youth). Risks of HIV-1 infection may result from direct exposure to contaminated blood through sharing of injection drug equipment and from unsafe sexual practices (while under the influence of drugs and/or in exchange for drugs). Reducing the risk of HIV-1 infection that is associated with illicit drug use requires prevention education and prompt engagement in treatment. Providing patients with education, instruction on decontamination of used injection drug equipment, improved access to sterile syringes and needles, and postexposure prophylaxis may decrease their risk of acquiring HIV-1 infection. Pediatricians should assess risk behaviors as part of every health care encounter, including queries about tobacco, alcohol, and marijuana use. The risks and benefits of postexposure prophylaxis with antiretroviral drugs should be considered for youth with a single recent (within 72 hours) high-risk exposure to HIV-1 through sharing needles/syringes with an HIV-1-infected individual or having unprotected intercourse with an individual who engages in injection drug use. Such prophylaxis must be accompanied by risk-reduction counseling, appropriate referrals for treatment, and evaluation for pregnancy and associated sexually transmitted infections. There is an urgent need for more substance-abuse prevention and treatment programs, legislation that facilitates unencumbered access to sterile syringes, and expedient availability of reproductive health care services for sexually active youth, including voluntary HIV-1 counseling and testing.