For several decades, clinicians have been prescribing hormone therapy to postmenopausal women for approved indications, including the alleviation of vasomotor symptoms, relief of vaginal dryness and prevention of osteoporosis. Numerous publications have demonstrated that estrogen also induces favorable effects on lipids, the endothelium, cardiovascular outcomes, quality of life, cognition, skin and urinary incontinence. As a result of these findings, clinicians began adding each of these outcomes to their list of possible benefits of hormone therapy in postmenopausal women. Results from the Women's Health Initiative significantly changed this treatment paradigm and opened the door for new, innovative therapies for the prevention of clinical conditions encountered by women of menopausal age. One such treatment option is the estrogen agonist/antagonist. In this regard, investigators and clinicians alike seek a therapy that will act like estrogen in all the 'right' tissues and act as an estrogen antagonist in tissues in which estrogen action results in adverse events. This review describes the molecular actions of estrogen agonists/antagonists, discusses the current clinical data regarding the effect of these compounds on menopause-associated outcomes, and describes what is currently known about the effects of combining estrogen with an estrogen agonist/antagonist.