Decision-analytic models are increasingly used to inform health policy decisions. These models synthesize available data on disease burden and intervention effectiveness to project estimates of the long-term consequences of care, which are often absent when clinical or policy decisions must be made. While models have been influential in informing US cancer screening guidelines under ideal conditions, incorporating detailed data on real-world screening practice has been limited given the complexity of screening processes and behaviors throughout diverse health delivery systems in the United States. We describe the synergies that exist between decision-analytic models and health care utilization data that are increasingly accessible through research networks that assemble data from the growing number of electronic medical record systems. In particular, we present opportunities to enrich cancer screening models by grounding analyses in real-world data with the goals of projecting the harms and benefits of current screening practices, evaluating the value of existing and new technologies, and identifying the weakest links in the cancer screening process where efforts for improvement may be most productively focused. We highlight the example of the National Cancer Institute–funded consortium Population-based Research Optimizing Screening through Personalized Regimens (PROSPR), a collaboration to harmonize and analyze screening process and outcomes data on breast, colorectal, and cervical cancers across seven research centers. The pairing of models with such data can create more robust models to not only better inform policy but also inform health care systems about best approaches to improve the provision of cancer screening in the United States.