There are meaningful cancer-related disparities in the Appalachian region of the U.S. To address these disparities, the Appalachia Community Cancer Network (ACCN), a collaboration of investigators and community partners in five states (Kentucky, Ohio, Pennsylvania, Virginia, and West Virginia), is involved in increasing cancer education and awareness, conducting community-based participatory research (CBPR), and creating mentorship and training opportunities. The primary objective of this paper is to describe cancer-related disparities in the Appalachian region of the U.S. as an example of the disparities experienced by underserved, predominantly white, rural populations, and to describe ACCN activities designed to intervene regarding these disparities. An ACCN overview/history and the diverse activities of ACCN-participating states are presented in an effort to suggest potential useful strategies for working to reduce health-related disparities in underserved white populations. Strengths that have emerged from the ACCN approach (e.g., innovative collaborations, long-standing established networks) and remaining challenges (e.g., difficulties with continually changing communities, scarce resources) are described. Important recommendations that have emerged from the ACCN are also presented, including the value of allowing communities to lead CBPR efforts. Characteristics of the community-based work of the ACCN provide a framework for reducing health-related disparities in Appalachia and in other underserved white and rural populations.