Arsenic ranks as the number one toxic environmental contaminant. In humans, arsenic exposure is associated with various forms of cancer, cardiovascular and skin diseases, neuropathies of the central nervous system, and genotoxic and immunotoxic effects. Although a well recognized human carcinogen, arsenic itself is not a potent mutagen and has been thought to act through epigenetic mechanisms that modify DNA methylation patterns, perhaps in conjunction with DNA-damaging agents. To develop preliminary support for a more thorough examination of this hypothesis, we have measured the effect of submicromolar and low-micromolar concentrations of arsenite on the methylation status of DNA and the biochemical reactions that regulate it. We find that arsenic causes the depletion of S-adenosylmethionine, the main cellular methyl donor, and represses the expression of the DNA methyltransferase genes DNMT1 and DNMT3A. Possibly as a consequence of these two complementary mechanisms, long-term exposure to arsenic results in DNA hypomethylation.