The purpose of this study was to identify ways Indigenous theoretical perspectives may guide current and future substance abuse prevention programs. As the majority of current theories guiding substance abuse prevention programs in American Indian and Alaska Native communities stem from Western ideologies and lack Indigenous perspectives, there is a paucity of research on theoretical underpinnings for Indigenous perspectives in AI/AN communities and their potential role in substance abuse prevention programming. It is well known that when programs are theoretically connected to the communities in which they are implemented, they are more likely to be accepted, accurately measured, and sustained for longer periods of time. Using a multi-method approach, in-depth qualitative interviews were conducted, followed by a content analysis of interviewee publications, and member check interviews to validate findings. Participants were asked about their perceptions on the role of theory in substance abuse prevention in American Indian and Alaska Native communities; with a focus on what Indigenous perspectives would look like in current and future programming. Results provided evidence of a complex, yet essential, topic area in which additional future studies are necessary. Identification of missing or lacking cultural elements and future recommendations are provided. Implications from the current study show the need for integration of Indigenous perspectives into substance abuse prevention programs for American Indian and Alaska Native communities.