In this article, we test the utility of Agnew's general strain theory to explain suicidal behaviors among American Indian youth. Data from 721 American Indian adolescents from the Midwest and Canada were collected in partnership with participating reservations/reserves and a research team. We investigate the effects of strains/stressors on suicide, including tests of mediating effects of negative emotions on relationships between stressors and suicidality. We found that several strains/stressors were related to suicidality, including coercive parenting, caretaker rejection, negative school attitudes, and perceived discrimination. We also found that depressive symptoms and anger mediated the effects of several key predictors of suicidality. We discuss the theoretical and policy implications of our work for the general strain theory and for American Indian suicide in general.