The physiological effects of progestins are mediated by the progesterone receptor, a member of the steroid/nuclear receptor superfamily(1). As progesterone is required for maintenance of pregnancy, its receptor has been a target for pharmaceuticals(2). Here we report the 1.8 Angstrom crystal structure of a progesterone-bound ligand-binding domain of the human progesterone receptor. The nature of this structure explains the receptor＇s selective affinity for progestins and establishes a common mode of recognition of 3-oxy steroids by the cognate receptors. Although the overall fold of the progesterone receptor is similar to that found in related receptors(3-6), the progesterone receptor has a quite different mode of dimerization(3,6). A hormone-induced stabilization of the carboxy-terminal secondary structure of the ligand-binding domain of the progesterone receptor accounts for the stereo-chemistry of this distinctive dimer, explains the receptor＇s characteristic pattern of ligand-dependent protease resistance and its loss of repression(7,8), and indicates how the anti-progestin RU486 might work in birth control. The structure also indicates that the analogous 3-keto-steroid receptors may have a similar mechanism of action.