Despite a recent increase in the clinical use of progesterone in pregnant women and premature neonates, very little is understood about the potential role of this hormone and its receptors in neural development. Findings from rodent models indicate that the brain is indeed sensitive to progesterone during critical periods of development and maturation. Dramatic sex differences in progesterone receptor (PR) expression, in which males express higher levels of PR than females in specific regions, suggest that PR may play an important role in the sexual differentiation of brain and behavior and that the expression of PR may be one mechanism by which testicular hormones masculinize the brain. PR is also transiently expressed during fetal and neonatal development in areas of the brain associated with cognitive behaviors. PR protein and mRNA are expressed in pyramidal cell layers of perinatal cortex in an anatomically and developmentally specific manner, generating the intriguing hypothesis that progesterone is essential for normal cortical development. Basic research elucidating a potential role for progesterone and PR in developing brain is reviewed in light of the clinical use of this hormone. The necessity for future research integrating findings from the bench and the bedside is evident.