In this article we review three categories of American Indian/Alaska Native (AIAN) substance abuse prevention programs: (1) published empirical trials; (2) promising programs published and unpublished that are in the process of development and that have the potential for empirical trials; and (3) examples of innovative grassroots programs that originate at the local level and may have promise for further development. AIAN communities are taking more and more independent control of substance abuse prevention. We point out that European American prevention scientists are largely unaware of the numerous grassroots prevention work going on in AIAN communities and urge a paradigm shift from adapting European American prevention science "best practices" to creating cultural "best practices" by working from inside AIAN communities.