Estrogen's role in the sex differences observed in autoimmune diseases such as systemic lupus, multiple sclerosis, and rheumatoid arthritis have remained unclear. Complicating the understanding of the immunomodulatory effects of estrogen are (1) the effects of estrogen on multiple components of the immune response; (2) its varied effects on different systems in which it appears pro-autoimmune, as in murine lupus, or anti-inflammatory, as in EAE; and (3) its effects on other hormones which are potentially immunomodulatory. Recent reports have shed light on the role of estrogen in the modulation of lymphocyte survival and expansion and in the elaboration of Th1 versus Th2 cytokines and on the mechanisms by which estrogen can activate via multiple signaling and genomic pathways in immune cells.