Kentucky ranks first in the U.S. in overall cancer incidence and mortality rates. Areas of the state that fall within the Appalachian Region, along Kentucky's eastern border, experience disproportionately high rates of cancer compared to non-Appalachian counties. Purpose: This pilot study investigates whether oral history interviews can be used to understand perspectives on cancer among residents of Appalachian Kentucky. In 2020, participants (n = 5) who identified as being from and/or having strong connections to Appalachian Kentucky were recruited to participate in this pilot study. Participants included individuals working in cancer-related fields, oncology professionals, and those with personal cancer experience. Using an oral history approach, subjects were asked about challenges within Appalachia that contribute to high rates of cancer regionally. Interviews were analyzed using qualitative content analysis, and data were condensed into themes, subthemes, and subtopics. Relational content analysis was then used to illustrate relationships between the problems being faced in Appalachia and their contributing factors, with potential solutions to those problems. Six key themes emerged from analysis of the oral history interviews: (1) problems being faced in Appalachia; (2) contributing factors; (3) potential solutions; (4) Appalachian disposition; (5) experiences with and thoughts on cancer; and (6) defining success v. the future without changes (intervention). A further 25 subthemes were identified from within these themes. Taken together, these themes and subthemes point to potential areas for specific intervention to shift Appalachia's cancer burden. This pilot study demonstrates potential benefit in using oral history interviews to elucidate Appalachian Kentuckians' perspectives on cancer. From the nuanced insights gained through this method, a set of culturally appropriate interventions were identified that could address the disproportionate cancer burden in the region. Future studies using an oral history approach could aim to reveal other specific aspects of how cancer impacts individuals, families, and communities.