Arsenic is the most ubiquitous environmental toxic substance. Arsenic is ubiquitous in water, soil and food and ranks first on the Environmental Protection Agency's Superfund Priority List of Hazardous Substances. Arsenic(III) S-adenosylmethionine (SAM) methyltransferase (AS3MT in animals and ArsM in microbes) is one of the key enzymes in arsenic biotransformations, catalyzing the methylation of inorganic arsenite to methyl, dimethyl and trimethyl products. As(III) methyltransferases are found in members of every kingdom, from bacteria to humans (EC 2.1.1.137). In the human liver, hAS3MT converts inorganic arsenic into more the toxic and carcinogenic methylated species. We have determined the X-ray crystal structures of CmArsM from the thermophilic eukaryotic alga Cyanidioschyzon merolae and CrArsM from the eukaryotic green alga Chlamydomonas reinhardtii. These two ArsMs are orthologs of hAS3MT. Analysis of their structures in various ligand-bound forms allowed us to develop a new hypothesis for catalysis involving a disulfide bond cascade. A homology model of hAS3MT was built on the structure of CmArsM with bound PhAs(III) (PDB ID: 4KW7). Interestingly, the model of human AS3MT has a cleft between the N-terminal and C- terminal domain that we propose is an allosteric site that controls the activity of AS3MT. We docked small molecules available in the NIH database with the hAS3MT model and found that they bind in the proposed allosteric site, consistent with a role for that site in regulating AS3MT catalysis. Supported by National Institutes of Health grants R01 GM55425 and R01 ES023779 to B.P.R. and HWCOM Pilot Funding to C.P. We acknowledge the synchrotron beam lines at APS, Chicago and ALS, Berkeley for data collection.