Ever since the discovery of estradiol and the elucidation of its chemical structure, there has been a great deal of interest in its mechanism of action and its potential therapeutic value. It is now well established that estrogens have many different functions in many different cell-types. With respect to the potential use of estrogens as therapeutics, there is an interest in controlling reproductive function, bone metabolism, cardiovascular disease, as well as in the prevention of hot flushes, mood changes and Alzheimer s disease. For over a decade, it was believed that estrogens signal through a a single estrogen receptor, now referred to as ERalpha, which belongs to a family of ligand-activated transcription factors. More recently, however, a second estrogen receptor ERbeta was identified. The current review describes similarities as well as differences between these two distinct estrogen receptors. Both ERalpha and ERbeta bind 17beta-estradiol with high affinity and they bind to classical estrogen response elements in a similar if not identical fashion. However, there are also major differences between ERalpha and ERbeta for instance with respect to their tissue distribution, the phenotype of the corresponding knock-out mice and their transcriptional activities. It is anticipated that a better understanding of these two receptors will eventually lead to more selective ways of modulating physiological processes which are influenced by estrogens. For this purpose, the development of ERalpha and ERbeta specific ligands, both agonists as well as antagonists, will be of great importance.