Patient navigators—individuals who assist patients through the healthcare system to improve access to and understanding of their health and healthcare—are increasingly used for underserved individuals at risk for or with cancer. Navigation programs can improve access, but it is unclear whether they improve the efficiency and efficacy of cancer diagnostic and therapeutic services at a reasonable cost, such that they would be considered cost-effective. In the current study, the authors outline a conceptual model for evaluating the cost-effectiveness of cancer navigation programs. They describe how this model is being applied to the Patient Navigation Research Program, a multicenter study supported by the National Cancer Institute's Center to Reduce Cancer Health Disparities. The Patient Navigation Research Program is testing navigation interventions that aim to reduce time to delivery of quality cancer care (noncancer resolution or cancer diagnosis and treatment) after identification of a screening abnormality. Examples of challenges to evaluating cost-effectiveness of navigation programs include the heterogeneity of navigation programs, the sometimes distant relation between navigation programs and outcome of interest (eg, improving access to prompt diagnostic resolution and life-years gained), and accounting for factors in underserved populations that may influence both access to services and outcomes. In this article, the authors discuss several strategies for addressing these barriers. Evaluating the costs and impact of navigation will require some novel methods, but will be critical in recommendations concerning dissemination of navigation programs. Cancer 2009. © 2009 American Cancer Society.