HIV and sexual risk continue to be central threats to the health and well-being of adolescents in the United States and abroad. Great strides have been made in creating interventions that reduce contracting and transmitting the deadly virus among adolescents. Numerous interventions have been designed and evaluated, with many having positive results in reducing adolescents' HIV risk behavior. However, the complexity of adolescents as well as limited effects on many sexual risk outcomes indicate that much more work needs to be done. This article provides a review of the literature on interventions among adolescents, summarizing why adolescents provide a unique challenge for HIV prevention, the intervention approaches that have been taken, and the challenges and recommendations for the future as the field confronts the neurobiologic dimension of risk.