Women now spend more than one-third of their lives in the postmenopausal years, and the decline of endogenous estrogen production during menopause is accompanied by a series of functional disorders that affect the quality of life. These symptoms could be alleviated or even totally suppressed by menopausal hormone therapy (MHT), initially based on natural estrogens extracted from the urine of pregnant mares (mainly in the USA, using the oral route) and later from the synthesis of the natural estrogen, 17β-estradiol (mainly in Europe, in particular using the transdermal route). Estrogen receptor (ER) α is the main receptor mediating the physiological effects of estrogens. ERα belongs to the nuclear receptor superfamily and activates gene transcription in a time and tissue-specific manner through two distinct activation functions (AF), AF1 and AF2. In addition to these classical genomic actions, ERα also mediates membrane initiated signaling enabling rapid actions of estrogen, potentially along or in interaction with other receptors. Here, we provide a brief historical overview of MHT, and we then highlight recent advances in the characterization of new treatments based on the association of estrogens with selective estrogen receptor modulators (SERMs) or on the modulation of nuclear or membrane ERα.