Background: American Indian children and adolescents are at risk for obesity, type 2 diabetes, hypertension, elevated cholesterol, and smoking, all of which are risk factors for cardiovascular disease. Objective: To address these health issues, we developed, implemented, and evaluated a culturally appropriate cardiovascular disease curriculum called "In Our Voice" for American Indian students in grades 7 through 12. The curriculum consisted of 16 modules lasting 50 minutes each, and it was implemented as a pilot test at five sites in two western states. Results: We faced many challenges to success, including competing demands for instructional time and classrooms, which prevented two schools from completing the curriculum. Two notable findings emerged: students preferred a multicultural focus over a culturally tailored focus, and they desired more interactive educational materials. Conclusion: Recommendations for successfully implementing an innovative curriculum include ensuring the ongoing presence of researchers at school sites, funding an internal curriculum champion at every site, and maintaining student advisory boards to communicate student feedback to researchers.