IMPORTANCE: Although cancer remains the most common cause of disease-related death in adolescents and young adults (AYAs) in high-income countries, their overall survival rates continue to increase and now exceed 80% at 5 years in several high-income countries. This has been accomplished through progressive improvements in active treatment and supportive care, although accrual rates to therapeutic clinical trials remain disappointing. Recognition of the unique distribution of diseases in the AYA population with cancer and further understanding of the distinctive biology of cancers in AYAs will lead to continuing gains in clinical outcomes. OBSERVATIONS: Many of the challenges faced by AYAs with a diagnosis of malignant disease are shared by others with chronic medical conditions and even their healthy peers, such as a sense of invulnerability that may contribute to delays in diagnosis. A particular need for psychological support has been identified for AYAs with cancer, even after active therapy has been completed and especially in the context of palliative care. Notable needs also include fertility preservation and navigation through the multiple transitions in the cancer journey. Additionally, there is a "cost of cure." This is not only in the form of short-term, treatment-related morbidity and mortality but also in the burden of "late effects," including second cancers, that compromise quality of life and limit life expectancy. Establishing clinical programs devoted to AYAs with cancer, with complementary educational initiatives, will strengthen the advances made. It is anticipated that clinical trial accrual will increase substantially, providing further gains in survival. Likewise, addressing the challenges of survivorship, including secondary prevention of long-term morbidity and mortality, will lead to additional improvements in clinical outcomes. CONCLUSIONS AND RELEVANCE: Transferring this knowledge to the care of an estimated 1 million incident cases of cancer in AYAs worldwide, most of whom do not live in high-income countries, remains a considerable challenge.