BACKGROUND: The Spirit of E.A.G.L.E.S. is a National Cancer Institute funded Special Populations Network. Prior to its inception, there was limited infrastructure available to American Indian and Alaska Native populations to support cancer control activities. METHODS: Awareness has been raised about the burden of cancer in this special population. RESULTS AND CONCLUSIONS: Changes have started to support truly comprehensive cancer control across the cancer care continuum and will drive future community-based, participatory action research.