Adolescents and young adults (AYAs) with cancer have inferior survival as compared to children. The reasons for this survival gap are multifactorial and related to psychosocial aspects, patient- and disease-related biological characteristics as well as to therapeutic approaches within this age span. Non-Hodgkin's lymphoma (NHL) comprises approximately 7% of cancer among AYAs, and patient allocation and therapy vary between health systems. In this systematic review we focus on the current biological and clinical knowledge relevant to AYAs with NHL applying these data to the clinical approach and practice. Data are insufficient to recommend a pediatric or an adult approach for AYAs with diffuse large B-cell lymphoma and anaplastic large cell lymphoma. Dose-adjusted EPOCH-R seems to be a promising, radiation-free approach for AYAs with primary mediastinal B-cell lymphoma. Limitations in data interpretation include the lack of interventional trials tailored specifically for the AYA population and the lack of uniform criteria for staging and response assessment in pediatric and adult trials.