Adolescents and young adults (AYAs) who have cancer face a distinct set of challenges beginning during the initial diagnosis, extending throughout treatment, and continuing into survivorship. Owing to significant strides made in cancer therapy in recent decades, more than 80% of this group will go on to become long-term survivors. Despite these improvements, however, many AYAs continue to have poorer outcomes when compared with older and younger patients. The purpose of this article is to underscore the unique set of multifaceted obstacles that this vulnerable group encounters and to pinpoint critical areas of attention and intervention throughout the health care journey. Moreover, it aims to highlight the importance of the role of the primary care provider as a constant partner in safeguarding the long-term physical and mental health of this diverse population within a complex and, at times, trying health care system. [Pediatr Ann. 2022;51(1):e27-e33.].