Selective estrogen receptor modulators (SERMs), which lack the estrogen steroid moiety yet retain the ability to bind the estrogen receptor (ER), are known to confer mixed ER agonist or antagonist effects depending on the target tissue. The tissue-selective effects of SERMs have led to considerations in the clinical profile of an ideal SERM, which would have ER agonist activity in tissues where mimicking the action of estrogens is desirable, and ER neutral or antagonist activity in tissues estrogens have been shown to adversely stimulate. A number of newer SERMs, including bazedoxifene, lasofoxifene, ospemifene, and arzoxifene, are currently in clinical development for the prevention and treatment of postmenopausal osteoporosis and for other indications. Although the possibility of developing a single agent that has all of the desired characteristics of an ideal SERM seems to be unlikely, progress in the clinical development of SERMs targeted to the ER suggests that these newer compounds may have attributes that represent an improvement relative to existing SERMs. Further clinical investigation will help to clarify the relative benefits and risks of novel SERMs in development within specific indications.