Systemic lupus erythematosus is a chronic relapsing autoimmune disease that primarilyafflicts women, and both a genetic predisposition and appropriate environmentalexposures are required for lupus to develop and flare. The genetic requirement isevidenced by an increased concordance in identical twins and by the validation of atleast 35 single-nucleotide polymorphisms predisposing patients to lupus. Genes alone,though, are not enough. The concordance of lupus in identical twins is oftenincomplete, and when concordant, the age of onset is usually different. Lupus is alsonot present at birth, but once the disease develops, it typically follows a chronicrelapsing course. Thus, genes alone are insufficient to cause human lupus, andadditional factors encountered in the environment and over time are required toinitiate the disease and subsequent flares. The nature of the environmentalcontribution, though, and the mechanisms by which environmental agents modify theimmune response to cause lupus onset and flares in genetically predisposed peoplehave been controversial. Reports that the lupus-inducing drugs procainamide andhydralazine are epigenetic modifiers, that epigenetically modified T cells aresufficient to cause lupus-like autoimmunity in animal models, and that patients withactive lupus have epigenetic changes similar to those caused by procainamide andhydralazine have prompted a growing interest in how epigenetic alterations contributeto this disease. Understanding how epigenetic mechanisms modify T cells to contributeto lupus requires an understanding of how epigenetic mechanisms regulate geneexpression. The roles of DNA methylation, histone modifications, and microRNAs inlupus pathogenesis will be reviewed here.