Background: Indigenous people experience the greatest cardiometabolic disease disparity in the Unites States, yet high cardiometabolic disease risk factors do not fully explain the extent of the cardiometabolic disease disparity for Indigenous people. Stress, trauma, and racism occur at high rates within Indigenous communities and have not been well explored as significant contributors to cardiometabolic disease disparities despite emerging literature, and therefore will be described here. Methods: This descriptive study explores the relationship between cardiometabolic disease risks and Indigenous-specific stressors (e.g., early childhood stress and trauma, adulthood stress and trauma, and historical and intergenerational trauma) using current literature. Indigenous-specific protective factors against cardiometabolic disease are also reviewed. Results. Increasing research indicates that there is a relationship between Indigenous-specific stressful and traumatic life experiences and increased cardiometabolic disease risk. Mental health and psychophysiology play an important role in this relationship. Effective interventions to reduce cardiometabolic disease risk in Indigenous communities focus on ameliorating the negative effects of these stressors through the use of culturally specific health behaviors and activities. Conclusions: There is increasing evidence that cultural connection and enculturation are protective factors for cardiometabolic disease, and may be galvanized through Indigenous-led training, research, and policy change.