This article reviews publications dating back more than a century describing investigations of the endometrium, including those examining the relationship between endometrial hyperplasia and carcinoma, the influence of estrogens on the endometrium, and strategies for protecting the endometrium from unopposed estrogen stimulation. Endometrial hyperplasia and carcinoma studies date from before 1900. The influence of endogenous estrogens on the endometrium became evident with observations of endometrial hyperplasia and/or carcinoma in women with estrogen-secreting tumors or polycystic ovarian disease. Later, observational studies and randomized, controlled trials suggested a relationship between unopposed estrogens and endometrial cancer and hyperplasia. The first, and to date only, effective clinical strategy for protecting the endometrium from unopposed estrogen stimulation has been the use of progestins. A new approach for endometrial protection in menopausal therapy is the pairing of a selective estrogen receptor modulator (SERM) with estrogen(s), also known as a tissue selective estrogen complex (TSEC). Effective protection of the endometrium as well as treatment of menopausal symptoms and prevention of osteoporosis would be key elements for a clinically useful TSEC.