At menopause many women experience undesired symptoms such as hot flashes and those associated with vulvovaginal atrophy, and are susceptible to loss of bone mass. Menopausal therapies to date include various estrogen and estrogen-progestin (progesterone congener) formulations. However, both physicians and women became concerned about hormone-related therapies following publication of data from the Women's Health Initiative. Thus, the need exists for alternative therapies for postmenopausal women. Tissue-selective estrogen complexes (TSECs) are the pairing of estrogen(s) with a selective estrogen receptor modulator (SERM). The goal of developing a TSEC is to provide the clinical benefits of each of its components with improved tolerability. This goal can potentially be achieved by the result of the different molecular and cellular activities of the treatment's estrogen and SERM components. The therapeutic profile of a TSEC would optimally include relief of hot flashes, treatment of vulvovaginal atrophy and its symptoms, and prevention of bone loss, while providing safety for the endometrium and breast. Recent data indicate that the TSEC containing the SERM bazedoxifene and conjugated estrogens relieves hot flashes, improves vulvovaginal atrophy and its symptoms, and prevents loss of bone mass without stimulating the endometrium. This article reviews the current options for menopausal treatment as well as the environment that has driven the most recent evolution of new therapies for menopausal women, including the most recent development of the TSEC bazedoxifene and its early preclinical and clinical data.