While the placenta expresses many of the membrane transporters for biogenic amines, the contribution of placental uptake to intrauterine catecholamine clearance was unknown. We determined NET development in the ovine placenta and frontal cortex of the fetus as nisoxetine (NSX) binding to purified plasma membranes. NSX bound to a single, high affinity binding site. Placental binding was greater than brain (25±6 vs 2±0.5 pmole/mg protein). Kd's were similar. To determine the role of placental transport in vivo, we determined the kinetics of labeled norepinephrine (NE) uptake by the fetus and placenta. Total clearance was 99±8 ml/kg/min. Placental uptake represented > 50% of total clearance. Both desipramine and cocaine blocked > 50% of placental reuptake confirming that more than 50% of placental uptake is transporter dependent. To confirm the molecular basis for placental transport, we screened an ovine placental cDNA library with the human NET cDNA and with oligonucleotides based on NET sequence. Southern blot of an EcoR1 digest of ovine genomic DNA revealed one major and two minor bands. We have isolated and partially sequenced an NET clone and a clone which is homologous to and transports serotonin. We conclude: 1) The placenta expresses amine transporters including the “neuronal” NET; 2) Placental NET mediated transport is significant in maintenance of fetal homeostasis; 3) Drugs like cocaine which block both fetal and placental NE clearance may have exaggerated adverse fetal consequences. Supported by DA 07753.