Reducing colorectal cancer mortality by promoting screening has been a national goal for two decades. The NCI’s Population-Based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium is the first federal initiative to foster coordinated, transdisciplinary research evaluating the entire cancer screening process in community settings. PROSPR is creating a central data repository to facilitate research evaluating the breast, cervical, and colorectal cancer screening process across different patient populations, provider types, and delivery systems. Data are being collected and organized at the multiple levels in which individuals are nested (e.g., healthcare systems, facilities, providers, and patients). Here, we describe a conceptual model of the colorectal cancer screening process guiding data collection and highlight critical research questions that will be addressed through pooled data. We also describe the three research centers focused on colorectal cancer screening with respect to study populations, practice settings, and screening policies. PROSPR comprehensively elucidates the complex screening process through observational study, and has potential to improve care delivery beyond the healthcare systems studied. Findings will inform intervention designs and policies to optimize colorectal cancer screening delivery and advance the Institute of Medicine’s goals of effective, efficient, coordinated, timely, and safe health care with respect to evidence-based cancer screening.