Systemic lupus erythematosus (SLE) is a prototypical systemic autoimmune disease that affects multiple organs and is characterized by episodic flares and elevated morbidity. The etiology of SLE is only partly known. In this context, recent attention has been paid to the importance of environmentally induced epigenetic modifications as significant contributors to the disease pathogenesis in genetically predisposed individuals. Here we review what is currently known on the role of epigenetics in SLE, and the investigations aimed at possibly targeting epigenetic mechanisms and/or related biomarkers to improve the monitoring, management and, ultimately, the prognosis of SLE.