Indigenous communities often face disproportionate challenges across a variety of health domains, and effective prevention strategies are sorely needed. Unfortunately, evidence is scant regarding what approaches are effective for these communities. A common approach is to take an evidence-based practice or program with documented effectiveness in other populations and implement it with Indigenous populations. While a science of intervention adaptation is emerging, there remains little guidance on processes for adaptation that strategically leverage both existing scientific evidence and Indigenous prevention strategies. In this paper, two case studies illustrate promising practices for adaptation, documenting the approaches of two research teams funded under the National Institutes of Health's initiative to support Intervention Research to Improve Native American Health (IRINAH). These teams worked with distinct Indigenous populations in the USA and Canada to culturally adapt the same prevention program, the Iowa Strengthening Families Program for Parents and Youth 10-14. The approaches of these two teams and the programs that resulted are compared and contrasted, and critical elements of adaptation in partnership with Indigenous communities are discussed.