The Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute collects data on cancer diagnoses, treatment, and survival for approximately 30% of the United States (US) population. To reflect advances in research and oncology practice, approaches to cancer control are evolving from simply enumerating the development of cancers by organ site in populations to including monitoring of cancer occurrence by histopathologic and molecular subtype, as defined by driver mutations and other alterations. SEER is an important population-based resource for understanding the implications of pathology diagnoses across demographic groups, geographic regions, and time and provides unique insights into the practice of oncology in the US that are not attainable from other sources. It provides incidence, survival, and mortality data for histopathologic cancer subtypes, and data by molecular subtyping are expanding. The program is developing systems to capture additional biomarker data, results from special populations, and expand biospecimen banking to enable cutting-edge cancer research and oncology practice. Pathology has always been central and critical to the effectiveness of SEER, and strengthening this relationship in this modern era of cancer diagnosis could be mutually beneficial. Achieving this goal requires close interactions between pathologists and the SEER program. This review provides a brief overview of SEER, focuses on facets relevant to pathology practice and research, and highlights the opportunities and challenges for pathologists to benefit from and enhance the value of SEER data.