Advances in antiretroviral medications have resulted in precipitous declines in HIV-associated morbidity and mortality; however, high levels of adherence are crucial to the success of HIV therapies. This article reviews published studies in the United States on HIV-infected youth (ages 13 to 24 years), focusing on adherence to antiretroviral regimens and interventions designed to enhance adherence. A systematic search yielded 21 articles published between 1999 and 2008 that reported data on medication adherence in HIV-infected youth, of which 7 described unique interventions to enhance medication adherence. Five thematic areas were identified to classify factors associated with adherence. Findings suggest psychosocial factors, in particular depression and anxiety, were consistently associated with poorer adherence across studies. Three types of adherence interventions with HIV-infected youth were found. Results suggest that examining adherence within the broader contextual issues present in the lives of youth, including HIV stigma and disclosure, caregiver stress, peer relations, mental health and substance use, and length of time on medications, may be most important to understanding how best to intervene with adherence among this population. Secondary HIV prevention interventions for youth represent a possible mode through which to deliver individually tailored adherence skill building and counseling to improve medication adherence.