Dramatic changes occur in the cardiovascular system at birth. The circulation changes from one characterized by the presence of central shunts, a relatively low combined ventricular output, right ventricular dominance, and pulmonary vasoconstriction, to a circulation in series with a high cardiac output equally divided between the two ventricles, and a greatly dilated pulmonary vascular bed. To understand the mechanisms that initiate these profound changes, studies that separate the components of the birth process in the chronically instrumented fetus must be continued, along with biochemical studies of isolated tissues to determine the cellular and subcellular events that mediate these changes. Understanding the many processes that control perinatal cardiovascular development will assist the physician in treating those infants in whom the transition from the fetal to the neonatal circulation is abnormal.