Given the female preponderance of systemic lupus erythematosus (SLE) in humans, the adverse effects of female gender and sex hormones in murine lupus, and numerous reports (retrospective, often anecdotal and uncontrolled) describing a temporal association between estrogen exposure and development or exacerbation of SLE, it is easy to accept that estrogens and SLE simply do not mix. While there are valid concerns regarding the use of exogenous estrogens in women with SLE, there are also potential health benefits to be considered. Several salutary effects of postmenopausal estrogens assume particular importance in SLE where the risks of osteoporosis, exaggerated by menopause (natural or cyclophosphamide-induced) and glucocorticoids, are substantial. Moreover, hormone replacement therapy (HRT) is associated with a 40% reduction in the risk of coronary artery disease, higher levels of high-density lipoprotein-cholesterol, and decreased levels of low-density lipoprotein-cholesterol and plasminogen-activator inhibitor type 1, benefits that should be especially applicable to post-menopausal women with SLE. More recent studies, albeit retrospective and absent the use of validated measures of disease activity, suggest that HRT may be well tolerated. In counseling patients regarding lupus and pregnancy, there are now clinical predictors of pregnancy outcome, and patients in remission tend to have good outcomes. The same principles may be true regarding advice on the use of HRT; patients with inactive or stable/moderate disease and at low risk for thrombosis may benefit without a change in lupus activity. Large prospective double-blind placebo controlled studies inclusive of all ethnic groups such as the Safety of Estrogens in Lupus Erythematosus-National Assessment (SELENA) trial should provide the basis for definitive recommendations.