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The Centers for Disease Control and Prevention initiated an economic analysis of the National Program of Cancer Registries (NPCR) in 2005 to estimate the true economic costs of operating a cancer registry, identify costs associated with registry activities, and evaluate the factors that may affect the efficiency of registry operations. We developed a Web-based NPCR cost assessment tool (NPCR-CAT) to collect activity-based cost data from all 48 NPCR registries. We collected data on registry funding, actual expenditures, and factors that may affect the efficiency of operating a central cancer registry. Key lessons learned during data collection and analysis include the importance of working closely with registry staff and balancing the need for standardized data elements with an understanding of individual registry characteristics. Our findings and lessons can be adapted to develop costing tools for other surveillance systems and cancer control programs, both domestically and internationally.