American Indians and Alaska Natives (AI/ANs) suffer from inordinate morbidity and mortality from various cancers. The Spirit of Eagles is a national Special Populations Network that has developed the community infrastructure to support culturally appropriate, long-range, comprehensive cancer control activities. Subcontracts were developed that involved major cancer centers, nonprofit organizations, policy boards, professional societies, and educators. Community-based cancer control grants were distributed through the Spirit of Eagles program. Community-based participatory research involved 38 communities in a broad range of cancer control activities. The key to long-range improvement in cancer morbidity and mortality in AI/AN communities lies in building infrastructure to support strong partnerships enabling community-based participatory research. Cancer 2006. (c) 2006 American Cancer Society.