Systemic lupus erythematosus is a poorly understood autoimmune disease, characterized by autoantibodies to nuclear antigens and immune complex deposition in organs like the kidney. Current evidence indicates that a pathologic CD4+T cell subset, characterized by impaired extracellular signal-regulated kinase (ERK) pathway signaling, DNA hypomethylation, and consequent aberrant gene expression contributes to disease pathogenesis. Hydralazine is a lupus-inducing drug that also decreases T cell DNA methylation by inhibiting the ERK signaling pathway, replicating the defect found in lupus T cells. These observations suggest that defective ERK pathway signaling alters gene expression in T cells by inhibiting DNA methylation, contributing to lupus pathogenesis. The signaling defect in hydralazine-treated and lupus T cells has now been mapped to protein kinase C δ. Understanding the mechanism causing decreased ERK pathway signaling in lupus may shed light on mechanisms contributing to disease development in genetically predisposed people.