Arsenic is the most ubiquitous environmental toxin and carcinogen. Human As(III) S-adenosylmethionine (SAM) methyltransferases (hAS3MT) methylates As(III) to trivalent methylated species that are more toxic and potentially more carcinogenic than inorganic arsenic. A synthetic hAS3MT gene was expressed, and the purified enzyme characterized. A new catalytic pathway is proposed in which the products are more toxic trivalent methylarsenicals, but arsenic undergoes oxidation and reduction as enzyme-bound intermediates.