Profound and consequential disparities in oral health persist for American Indians and Alaska Natives. Decades of epidemiological studies have documented rates of early childhood caries (ECC) among American Indian children that are more than six times higher than those for white children, and three times higher than the rates for the general US population. While there is alarming need among this population, and there is clear evidence that dental caries can be prevented, successful programmes for prevention are rare. This report will review caries trends among American Indian children and describe promising approaches that take into account culturally defined responses of AI/AN tribes and communities. The work of the Center for Oral Health Disparities will be described, with its emphasis on community and behavioral strategies that have proven successful for working with AI/AN populations in areas of other health needs.