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The roles of many environmental contaminants in increasing breast cancer risk remain controversial. Arsenic (As) is a major global environmental contaminant and carcinogen. We conducted a systematic review of the role of As and gene-arsenic interactions in susceptibility to breast cancer. Following a systematic literature search using well-defined inclusion/exclusion criteria, a total of 15 epidemiologic studies (two meta-analyses, three systematic reviews, three cohort studies, two case-control studies, and five cross-sectional studies) were reviewed. In addition, several animal, in vitro , in vivo , and in silico (i.e., computer modeling) studies provided mechanistic insights into the association between As and breast cancer. Our review suggests a possible overall main effect of As on breast cancer risk. The evidence for an effect of gene-As interactions on breast cancer risk is strong. Studies that measured levels of As metabolites among participants and/or evaluated interactions between As exposure and genetic or epigenetic factors generally reported positive associations with breast cancer risk. Our analysis of the Comparative Toxicogenomics and the Ingenuity Pathway Analysis Databases provided further evidence for As-gene interactions and their effects on breast cancer-related biologic pathways. Our findings provide potential leads for future epidemiologic studies of As-associated cancer risks and interventions to reduce population exposure., (© 2020 Walter de Gruyter GmbH, Berlin/Boston.)