Conjugated estrogens (CE) combined with the selective estrogen receptor modulator (SERM) bazedoxifene (BZA) is a new option for alleviating menopausal symptoms and preventing postmenopausal bone loss. The rationale for developing the tissue selective estrogen complex (TSEC) CE/BZA was to combine CE's benefits with the SERM's tissue-specific properties to offset estrogenic stimulation of endometrial and breast tissue. TSECs provide a progestin-free alternative to traditional estrogen-progestin therapy (EPT) in women with a uterus. Preclinical studies supported bazedoxifene as the SERM of choice and demonstrated that CE/BZA provided an optimal balance of estrogen receptor agonist/antagonist activity compared with other potential TSEC pairings. Initial clinical development of CE/BZA focused on determining the appropriate dose ratio that would demonstrate efficacy with minimal to no stimulation of the breast or endometrium. Clinical studies confirmed the efficacy of the selected doses for maintaining bone mass; relieving vasomotor symptoms, vulvar-vaginal atrophy, and dyspareunia; and improving sexual function in postmenopausal women. Reduction of hot flashes also translated into improved menopause-specific quality of life and sleep. Unlike EPT, the FDA-approved dose of CE 0.45 mg/BZA 20mg does not cause a change in breast density or the endometrium, or increase breast pain compared with placebo. In clinical trials up to 2 years, CE 0.45 mg/BZA 20 mg has a favorable tolerability profile and rates of coronary heart disease, venous thromboembolism, and amenorrhea similar to placebo. Therefore, CE 0.45 mg/BZA 20 mg is an effective, well-tolerated alternative to EPT for menopausal symptom relief and osteoporosis prevention for postmenopausal women with a uterus.