Purpose: This review aims to provide a broad overview of the issues and clinical challenges of nonadherence in adolescents and young adults (AYAs) with cancer. Nonadherence can reduce treatment efficacy, which places the patient at higher risk of relapse, adverse effects, and poor outcomes. Design: A review of the English-speaking literature between 1980 and 2008 was conducted to identify relevant publications, which were supplemented by reference and author searches. Results: Definition and measurement of adherence varies. Most studies have not clearly delineated an AYA age group (ie, 15-25 years) and have been dominated by leukemia and lymphoma samples. Estimates for nonadherence in this population range from 27% to 60%, with openness of family relationships and support found to predict adherence. Strategies to avoid, assess, and manage nonadherence are presented. Conclusion: Overall, the evidence base for adherence and strategies to promote it in AYAs with cancer is woefully lacking. There is a need for high-quality studies that target clinically important questions, randomized controlled trials of theoretically based interventions, and development and evaluation of training programs for oncology staff in the special issues faced by AYAs with cancer. © 2010 by American Society of Clinical Oncology.