American Indian and Alaska Native (AI/AN) populations bear a heavy burden of cardiovascular disease (CVD), and they have the highest rates of risk factors for CVD, such as cigarette smoking, obesity, and diabetes, of any U.S. population group. Yet, few randomized controlled trials have been launched to test potential preventive interventions in Indian Country. Five randomized controlled trials were initiated recently in AI/AN communities to test the effectiveness of interventions targeting adults and/or children to promote healthy behaviors that are known to impact biological CVD risk factors. This article provides a context for and an overview of these five trials. The high burden of CVD among AI/AN populations will worsen unless behaviors and lifestyles affecting CVD risk can be modified. These five trials, if successful, represent a starting point in addressing these significant health disparities.