Cancer screening interventions offer the potential for both risk and benefit. Research related to screening and cancer in children or adolescents/young adults (AYA) can approach any of several questions. One question to be addressed is whether population-based screening tests can be developed that would reduce incidence or mortality from cancer in children or AYA without causing undue risk to the healthy population and with reasonable cost-effectiveness. This has not yet proven to be possible, and some of the relevant considerations are discussed in this article. The second question concerns the use of screening tests commonly applied to the general population and the special considerations when applied in the context of children/AYA with cancer or of adult survivors. Finally, a third general area of research concerns the inclusion of specialized screening in the follow-up of survivors of cancer in children and AYA to address the potential for recurrences, new primaries, and long-term sequelae of treatment. Although current guidelines for screening in follow-up are derived from a blend of evidence and expert clinical opinion, it is likely that future guidelines will evolve as a result of clinically intense research that takes into consideration the needs of this very unique group. Cancer 2011;117(10 suppl):2275–80. © 2011 American Cancer Society.