Cancer continuously ranks among the top 10 leading causes of death in the United States. The burden of cancer is particularly elevated in the Commonwealth of Kentucky and its 54-county Appalachian region, where cancer is the leading cause of death. Kentucky’s high rates of cancer have been attributed to a wide range of socioeconomic, behavioral, environmental, and policy influences, resulting in numerous disparities. The present review specifically evaluates the burden of lung, colorectal, cervical, and head and neck cancers in Kentucky, along with resultant cancer control research and community outreach efforts conducted by the state’s only National Cancer Institute–designated cancer center using an adapted version of McLeroy’s Social-Ecological Model. Here, we categorize disparities and identify relevant intervention approaches based on their level of influence (ie, individual, community, and policy).