The neurochemical differentiation of bulbospinal noradrenergic and serotonergic neurons has been followed in first trimester human fetuses. Analysis of microdissected CNS regions revealed detectable levels of noradrenaline (NA) and serotonin (5-HT) in pons, medulla oblongata and throughout the spinal cord from 5-6 weeks of gestation. In all regions there was a pronounced increase in tissue levels of the monoamines, especially from 8-9 weeks on. 5-HT levels were lower than NA levels except for pons, where the opposite was true. With increasing fetal age, the results seemed less consistent because of considerable interindividual variations. Using immunohistochemical localization of tyrosine hydroxylase (TH), a marker for noradrenergic neurons, immature cell bodies were seen in the brain stem at the earliest stage studied, that is at 4 weeks of gestation. Several TH and 5-HT-immunoreactive (IR) cell groups were found in pons and medulla oblongata at 5 weeks. Significant structural differentiation of TH- and 5-HT-IR cell bodies was seen during the first trimester. Immunoreactive fibers began to appear at 5 weeks in the cervical spinal cord. At 6 weeks both types of fibers could be found in the white matter throughout the entire spinal cord while fibers in gray matter appeared at 9 weeks. The number of TH-IR fibers was considerably larger than the number of 5-HT-IR fibers. This is the first time the biochemical development of human bulbospinal monoaminergic neurons during the first trimester has been described. Continued investigations of the ontogenetic growth and differentiation of these human bulbospinal monoaminergic neurons will gain necessary insight into the genetically determined capacity for plasticity, potentially possible to activate later in life in response to spinal cord injury. Further, intraspinal transplantation of CNS tissue relevant to the severed spinal cord would by necessity entail selection of embryonic cell populations. Using such therapeutic strategies, detailed knowledge of the inherent capacities of the donor tissues will be crucial.