Residents of Appalachia, especially those in rural Appalachia, are generally considered to be medically underserved. In fact, cancer mortality in Appalachia, especially in rural Appalachia, is higher than it is in the remainder of the United States. Developing from the Appalachia Leadership Initiative on Cancer, the Appalachia Cancer Network (ACN) is a network of academic and community organizations that seek to conduct surveillance, intervention, and dissemination research to reduce this excess cancer burden in Appalachia. The purpose of this report is to (1) describe the approach to cancer control research in ACN, a Special Population Network, among the medically underserved of Appalachia, and (2) to put forward observations from this experience to enhance the research of other academic and community networks among underserved populations. ACN has instituted a conceptual model, organizational structure, and other methods to foster this research and to develop junior and community-based investigators. Important issues and questions related to the effectiveness of such research networks have also been articulated.