The ancestral status of estrogen receptor (ER) in the family of the steroid receptors has probably contributed to the pleiotropic actions of estrogens, and in particular of 17β-estradiol (E2). Indeed, in addition to their well described role in sexual development and reproduction, they influence most of the physiological processes. The pathophysiological counterpart of these actions includes prevention of osteoporosis, atheroma and type 2 diabetes,... but also promotion of uterus and breast cancer growth. Thus, the major challenge consists in uncoupling some beneficial actions from other deleterious ones, i.e. selective ER modulation. Tamoxifen and raloxifen are already used as they prevent the recurrence of breast cancer, and mimic estrogen action mainly on bone. Both E2 and tamoxifen exhibit a proliferative and thus protumoral action on the endometrium. Activation of ER alpha (ERα) and beta (ERβ) regulates target gene transcription (genomic action) through two independent activation functions AF-1 and AF-2, but can also elicit rapid membrane initiated steroid signals. In the present review, we attempted to summarize recent advances provided by the in vivo molecular "dissection" of ERα, allowing the uncoupling of some of its actions, and potentially paving the way to optimized selective ER modulators.