Cancer care disparities among rural populations are increasingly documented and may be worsening, likely because of the impact of rurality on access to state-of-the-art cancer prevention, diagnosis, and treatment services, as well as higher rates of risk factors such as smoking and obesity. In 2018, the American Society of Clinical Oncology undertook an initiative to understand and address factors contributing to rural cancer care disparities. A key pillar of this initiative was to identify knowledge gaps and promote the research needed to understand the magnitude of difference in outcomes in rural vs nonrural settings, the drivers of those differences, and interventions to address them. The purpose of this review is to describe continued knowledge gaps and areas of priority research to address them. We conducted a comprehensive literature review by searching the PubMed (Medline), Embase, Web of Science, and Cochrane Library databases for studies published in English between 1971 and 2021 and restricted to primary reports from populations in the United States and abstracted data to synthesize current evidence and identify continued gaps in knowledge. Our review identified continuing gaps in the literature regarding the underlying causes of rural–urban disparities in cancer outcomes. Rapid advances in cancer care will worsen existing disparities in outcomes for rural patients without directed effort to understand and address barriers to high-quality care in these areas. Research should be prioritized to address ongoing knowledge gaps about the drivers of rurality-based disparities and preventative and corrective interventions.