Over the past two decades, we have learned that estrogens play important physiological roles not only in women but also in men and that the biological effects of estrogen are mediated by not one but two distinct estrogen receptors (ERs), ERα and ERβ. Our appreciation of the physiological importance of estrogen and the mechanisms by which it acts has significantly increased over the years; however, we are only now beginning to decipher the roles of ERα and ERβ in different organs and to elucidate how selective ligands, acting through either of the two ERs, can prevent or treat various age- or sex-specific diseases. The specific roles of ERα and ERβ and the therapeutic potential of ER subtype-selective agonists in bone and metabolic homeostasis, depression, vasomotor symptoms, neurodegenerative diseases, and cancer are reviewed herein. It must be stated, however, that appropriate clinical studies are necessary to validate these compounds as agents for the prevention and treatment of diseases.