Although progesterone has been traditionally associated with the establishment and maintenance of mammalian pregnancy, a number of studies have implicated physiological roles of this steroid hormone in other reproductive events. At present most of the downstream molecular and cellular mechanisms by which progesterone exerts its effects are unclear; however, the progesterone signal is known to be mediated initially by the progesterone receptor (PR), a member of the nuclear receptor superfamily of transcription factors. In most tissues studied, the PR is induced by ovarian estrogen via the estrogen receptor (ER), thereby implying that many of the observed reproductive physiological responses attributed to PR could conceivably be due to the combined effects of progesterone and estrogen. Therefore, to define clearly the distinct roles of progesterone and estrogen in vivo and to understand better progesterone function in a physiological context, we recently have generated a novel mouse strain in which both forms of the PR were ablated using gene targeting/embryonic stem cell techniques. Surprisingly, both male and female embryos, homozygous for the PR null mutation, developed to adulthood at the normal Mendelian frequency with no deviation in the sex ratio. Although developmental defects have yet to be detected in the adult male PR homozygote, extensive reproductive abnormalities were observed in the female. The reproductive phenotypes consisted of an inability to ovulate, uterine hyperplasia and inflammation, severely limited mammary gland development and an impairment in the induction of a sexual behavioral response. Collectively, these results provide direct in vivo evidence for progesterone's role as a pleiotropic coordinator of diverse reproductive events that together ensure female fertility. Finally, we believe that this animal model will be an invaluable tool in exploring the effects of progesterone in physiological systems other than reproduction and may, in the future, help to redefine progesterone not just as a sex steroid hormone but also as a key regulator of diverse physiological processes.