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Arsenic intoxication represents a worldwide health problem and occurs mainly through drinking water. Arsenic, a metalloid and naturally occurring element, is one of the most abundant elements in the earth’s crust, whose toxicity depends on the reduction state. The trivalent arsenicals are more toxic than the pentavalent arsenicals. In the trivalent state, inorganic and organic arsenic may react with thiol groups in proteins inhibiting their activity, whereas inorganic arsenic in the pentavalent state may replace phosphate ions in several reactions. Arsenic induces various epigenetic changes in mammalian cells, both in vivo and in vitro, often leading to the development of various types of cancers, including skin, lung, liver, urinary tract, prostate, and hematopoietic cancers. Potential mechanisms of arsenic toxicity in cancer include genotoxicity, altered DNA methylation and cell proliferation, co-carcinogenesis, tumor promotion, and oxidative stress. On the other hand, the FDA-certified drug arsenic trioxide provides solutions for various diseases, including several types of cancers. Detoxification from arsenic includes chelation therapy. Recently, investigations of the capability of some plants, such as Eucalyptus camadulensis L., Terminalia arjuna L. and Salix tetrasperma L., to remove arsenic from polluted soil and water have been studied. Moreover, nanophytoremediation is a green technology including the nanoscale materials used for absorption and degradation of organic and inorganic pollutants, such as arsenic compounds. This brief review represents an overview of arsenic uses, toxicity, epigenetics, and detoxification therapies.