Progesterone participates in the regulation of several physiological processes in mammals. The biological response to progesterone is mediated by two forms of the progesterone receptor (PR) denominated PR-A and PR-B. The difference between them is that 164 amino acids of N-terminal of PR-B are absent in PR-A. Both PR isoforms are derived from a single gene but are generated from either alternative transcriptional or translational start sites, and are regulated by different estrogen-induced promoters. PR-B acts as a transcriptional activator in different cellular contexts whereas PR-A functions as a strong inhibitor of transcriptional activity. PR isoforms expression and function vary among target tissues such as the uterus, the mammary gland and the brain. The knowledge of the molecular mechanisms involved in the regulation of expression and function of PR isoforms will contribute to the understanding of fundamental biological processes such as sexual behavior and reproduction, and it will open the possibility of alternative therapies in fertility control as well as in the treatment of breast, endometrial and cerebral tumors.