Background: High-intensity, risk-based therapeutic strategies for childhood cancer have resulted in long-term survival rates that now approach 80%. However, the growing population of survivors is at a substantial risk for treatment-related complications that can significantly impact quantity and quality of survival. It is increasingly recognized that many of these complications result from complex interactions between therapeutic exposures and genetic susceptibility. Objective: This review is designed to increase general clinician awareness of the ongoing efforts by investigators to understand the interactions between therapeutic exposures and genetic susceptibility to therapy-related complications. Results: Most studies have relied on a biologically plausible candidate gene approach to evaluate genetic susceptibility. This has resulted in the identification of unique genetic polymorphisms that could alter metabolic pathways of therapeutic agents associated with specific adverse events. We highlight some of these findings and discuss their implications for future prevention strategies, as well as their role in elucidating the pathophysiology of these complex diseases. Conclusion: Research exploring the role of genetic susceptibility in the development of therapy-related adverse outcomes is still in its infancy. There is a need for continued efforts to study these outcomes in the context of complex gene-gene and gene-environment interactions unique to cancer survivors. A better understanding of the pathogenesis of these outcomes will help develop effective targeted prevention strategies. © 2009 Society of General Internal Medicine.