Economic and social marginalization among American Indians and Alaska Natives (AI/ANs) results in higher chronic disease prevalence. Potential causal associations between toxic environmental exposures and adverse health outcomes within AI/AN communities are not well understood. This review examines epidemiological literature on exposure to toxicants and associated adverse health outcomes among AI/AN populations. PubMed, Embase, Cochrane, Environment Complete, Web of Science Plus, DART, and ToxLine were searched for English-language articles. The following data were extracted: lead author's last name, publication year, cohort name, study location, AI/AN tribe, study initiation and conclusion, sample size, primary characteristic, environmental exposure, health outcomes, risk estimates, and covariates. About 31 articles on three types of environmental exposures met inclusion criteria: persistent organic pollutants (POPs), heavy metals, and open dumpsites. Of these, 17 addressed exposure to POPs, 10 heavy metal exposure, 2 exposure to both POPs and heavy metals, and 2 exposure to open dumpsites. Studies on the Mohawk Nation at Akwesasne; Yupik on St. Lawrence Island, Alaska; Navajo Nation; Gila River Indian Community; Cheyenne River Sioux; 197 Alaska Native villages; and 13 tribes in Arizona, Oklahoma, North Dakota, and South Dakota that participated in the Strong Heart Study support associations between toxicant exposure and various chronic conditions including cardiovascular conditions, reproductive abnormalities, cancer, autoimmune disorders, neurological deficits, and diabetes. The complex interplay of environmental and social factors in disease etiology among AI/ANs is a product of externally imposed environmental exposures, systemic discrimination, and modifiable risk behaviors. The connection between environmental health disparities and adverse health outcomes indicates a need for further study.