Cancer represents an increasingly important health problem impacting the health status of American Indians and Alaska Natives (AI/ANs). At the turn of the century and as recently as the 1950s, cancer was such an uncommon occurrence among AI/ANs that they were thought,to be immune. Today, malignant disease represents a leading cause of death among these peoples. This relatively sudden increase has left communities and health agencies unprepared. This paper presents the framework for approaching cancer control research among AI/ANs, including the development of accurate surveillance systems; enhanced public and professional education; research focused on risk-factor prevalence and etiology; improved communication between Native communities and researchers; comprehensive evaluation of cancer control programs; dissemination of successful intervention programs; and research to examine factors responsible for the low risk of specific cancers among Native populations. Moreover, results from a series of national surveys providing a comprehensive overview of the limited cancer control programs directed toward AI/AN populations are highlighted. Efforts to maximize the health status of American Indians and Alaska Natives through cancer control efforts will rely upon a cooperative approach between individual tribal groups along with the proactive involvement of federal and state public health agencies, as well as the support of appropriate private and nonprofit organizations.