Hormone therapy (HT) is the most effective treatment for menopausal symptoms, and reduces both spinal and non-spinal postmenopausal osteoporotic fractures. However, a Women's Health Initiative (WHI) trial revealed that progestin-containing HT is associated with higher incidences of breast cancer and coronary heart disease than those associated with placebo. Tissue selective estrogen complex (TSEC) is a novel progestin-free HT option composed of conjugated estrogens (CE) and a selective estrogen receptor modulator. CE at a dose of 0.45 mg combined with 20 mg of bazedoxifene was the first TSEC medication approved in the United States and Korea for women with moderate to severe menopause-related vasomotor symptoms (VMS) and for preventing postmenopausal osteoporosis. This review summarizes the clinical efficacy, safety, and tolerability of TSEC as obtained from the five SMART clinical trials.