Today we have to consider the existence of two estrogen receptors, alpha and beta, in our attempts to understand the role of estrogen receptors in physiology and pathology, and to explain the pharmacology of estrogens, antiestrogens, and SERMs. Both ERalpha and ERbeta belong to the large family of nuclear receptors that function as hormone-dependent transcription factors with important roles in the endocrine signaling system. Estrogen signaling is dependent on multiple mechanisms involving the two estrogen receptors and, perhaps, also other, non-estrogen receptor-related proteins. In the post-genomic era, with the help of technological advancements, we will see a dramatic increase in our understanding of the biological role of the two estrogen receptors, and in the function of estrogens, antiestrogens, and SERMs, which will significantly enhance our chances to develop designer drugs with dramatically improved therapeutic profiles.