There was a time when the classification of sex hormones was simple. Androgens were male and estrogens female. What remains true today is that in young adults androgen levels are higher in males and estrogen levels higher in females. More recently we have learned that estrogens are necessary in males for regulation of male sexual behavior, maintenance of the skeleton and the cardiovascular system, and for normal function of the testis and prostate. The importance of androgen in females was never in doubt, it is after all the precursor of estrogen as the substrate for aromatase, the enzyme that produces estrogen. In addition, the tissue distribution of androgen receptors suggests that androgens themselves are important in the ovary, uterus, breast, and brain. New information promises to clarify some of the complex issues of the physiological roles of estrogen and the contribution of estrogen to the development of neoplastic diseases in humans. The discovery of the second estrogen receptor, the creation of mutant mice defective in both estrogen receptors and in the aromatase gene, the solution of the structures of the ligand-binding domains of estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta), the finding of novel routes through which estrogen receptors can modulate transcription, and the identification of a man with a bi-allelic disruptive mutation of the ERalpha gene are but some of the milestones. This review focuses on the mechanistic aspects of signal transduction mediated by ERs and on the physiological consequences of deficiency of estrogen or estrogen receptor in the available mouse models.