Some forms of drug-induced lupus may be due to inhibition of T cell DNA methylation. DNA methylation modifies gene expression. In general, methylation of regulatory elements suppresses gene expression, while hypomethylation promotes gene expression. Methylation patterns are replicated during mitosis by a family of DNA methyltransferases, whose expression is regulated in part by signals transmitted through the extracellular signal-regulated kinase (ERK) pathway. Inhibition of DNA methylation during mitosis results in aberrant gene expression in the daughter cells, sometimes with pathologic consequences. A recent series of reports demonstrates that treating T lymphocytes with DNA methyltransferase inhibitors such as 5-azacytidine and procainamide, or ERK pathway inhibitors including hydralazine and the MEK inhibitor U0126, inhibits DNA methylation, alters gene expression, and induces autoreactivity. The autoreactive cells cause a lupus-like disease in animal models. Importantly, the same DNA sequences are demethylated in T cells from patients with active lupus, with identical effects on gene expression. These observations suggest that certain drugs and chemicals, and possibly as yet unidentified environmental toxins, can modify DNA methylation patterns through effects on DNA methyltransferase activity or expression, resulting in disordered gene expression and the subsequent development of a lupus-like disease.