Sex hormones – estrogens, progestins, androgens, and prolactin – have well-documented effects on the development, progression, or severity of systemic lupus erythematosus (SLE). These effects are complex and are confounded by in vitro and in vivo considerations that obscure a simple explanation of the sexual dichotomies in SLE. An overview of available experimental and clinical data suggests that low androgens and abnormalities in the prolactin-gonadal axis are the most consistent hormonal aberrations found in human SLE. Additional studies focusing on interactions of gonadal steroids with prolactin and other pituitary hormones should expand our understanding of the role of sex hormones in the pathogenesis of SLE and strengthen the potential of hormonal immunotherapy.