The metabolism of arsenicals, including their reduction and methylation has been extensively studied, and both classical and novel pathways of arsenic methylation are proposed. Arsenic methylation has been considered to be a detoxification process of inorganic arsenicals, although recent studies have indicated that trivalent methylated arsenicals, the intermediate products of arsenic methylation, are more toxic than inorganic arsenicals. In 2002, arsenite (+3 oxidation state) methyltransferase (As3MT) was discovered to be an enzyme responsible for arsenic methylation. This review focuses on current information on the function, genetic polymorphism, and alternative splicing of As3MT, all of which contribute to arsenic metabolism and toxicity.