Every year in Canada and the United States, about 26,000 adolescent and young adults (AYA) between ages 15 and 29 years are diagnosed with cancer. Although the majority of AYA cancer patients will survive their primary cancer, many will develop serious health problems or die prematurely secondary to their curative cancer therapy. Much is known about the long-term health outcomes after adolescent cancer. In contrast, there remain substantial gaps in our understanding of the long-term outcomes after most young adult cancers. To optimize the health and quality of life of AYA cancer survivors and improve upon curative cancer therapy, it is essential to further investigate the long-term outcomes of this population. Before embarking upon this endeavor, it is important for the investigator and the funding agency to be cognizant about some of the unique challenges in research of AYA cancer survivors. To this end, the authors present a brief overview of some of the key research challenges, discuss the strengths and limitations of using available AYA cohorts and databases, and highlight potential future directions. Cancer 2011;117(10 suppl):2295–300. © 2011 American Cancer Society.