Abstract: The frontiers of placental endocrinology have been enlarged in the last decade. The hypothesis that the placenta could produce typical neuronal substances has been largely confirmed. Indeed, human placenta is a source of brain, pituitary, gonadal, and adrenocortical hormones. Moreover, the synthesis of placental hormones is not simply autonomous but is sensitive to other signals. Both locally produced hormones and circulating substances actively influence placental hormone release. The local intraplacental mechanism of control is in many aspects comparable to the organization of the hypothalamus-pituitary-target organ axes. In fact, many hypothalamic [corticotropin-releasing factor (CRF), thyrotropin-releasing hormone (TRH), growth hormone-releasing factor (GRF), somatostatin, and gonadotropin-releasing hormone (GnRH)] and gonadal (inhibin, activin) hypophysiotropic hormones have been found in the human placenta. They are chemically identical and as biologically active as their hypothalamic/gonadal counterparts, and, when added to the placental cell cultures, modulate the release of both pituitary-like peptide hormones and gonadal/adrenal cortex-like steroid hormones. This model of interaction apparently corresponds to three different cell populations: the cytotrophoblast and the intermediate trophoblast, which produce the releasing and inhibiting factors, and the syncytiotrophoblast, which produces the peptide and steroid hormones. However, the histochemical findings often reveal that immunoreactive hormones are present in the different cell populations [human chorionic gonadotropin (hCG), GnRH]. Moreover, other typical neurohormones [neuropeptide Y (NPY), endogenous opioid peptides] have been found in human placenta and they also seem to participate in the regulation of placental hormone release. Hormonal communication within the placenta may be endocrine, paracrine, or autocrine. The presence of specific placental binding sites for the locally produced neurohormones and the presence of high intracellular second messenger [cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP)] concentrations support an endocrine/paracrine interaction. Moreover, the secretion of the various placental neurohormones and of the classical placental hormones may be affected by hormonal or neuronal substances originating from the mother or the fetus. Therefore, the placenta represents an extra source of hormones for the gestational unit. Once stimulated, placental hormones act on the placenta itself and enter the maternal and fetal circulation. The major efflux seems to be to the maternal bloodstream. Plasma GnRH and CRF levels, which generally are undetectable or very low in adults, are elevated in pregnant women. The values of plasma NPY and inhibin during pregnancy are higher than in nonpregnant women. These plasma hormone levels remain elevated throughout pregnancy and may increase during labor (CRF, NPY) or in maternal (diabetes, hypertension) or fetal (growth retardation) pathological conditions. All of these changes may be correlated to the placental source. Once in the circulatory system, the placental neurohormones may act on their usual target, the pituitary gland, or on the other receptors (brain, gastrointestinal and genitourinary tracts, and immune-related cells). To reduce this possible impact with normal endocrine function, the existence of circulating binding proteins has been hypothesized. This fascinating and complex neuroendocrine regulation of human pregnancy emphasizes the importance of the placenta. A correct placental hormonal functioning is essential for reproduction. The evidence that the placenta produces stimulatory and inhibitory factors opens new perspective in the investigation of the basic mechanisms controlling placental function. The potential clinical applications in the diagnosis and treatment of human pregnancy remain to be investigated.