The uptake of 3H-l-norepinephrine was examined in isolated perfused rat lungs, and the mechanism of uptake was compared with that previously found for 5-hydroxytryptamine. Most of the norepinephrine taken up by the lungs was rapidly deaminated and O-methylated, and the metabolic products were subsequently returned to the perfusate. The presence of iproniazid and tropolone markedly inhibited this metabolism; because the metabolites were released from the lungs more rapidly than was norepinephrine itself, these inhibitors appeared to increase the rate of uptake of the amine. The uptake of norepinephrine was a saturable, temperature dependent process with a Km of 1.11 x 10-6M and a Vmax measured during metabolic inhibition of 2.78 x 10-9 moles/g min-1. Uptake was inhibited by cocaine, imipramine, ouabain, and potassium free medium as well as by decreasing the sodium concentration or increasing the potassium concentration of the medium. Although normetanephrine reduced the uptake of norepinephrine, metaraminol had no effect. Autoradiography indicated that norepinephrine was taken up into endothelial and smooth muscle cells, but the mechanism of the uptake appeared to combine features characteristic of both extraneuronal and neuronal uptake. The mechanism of uptake of norepinephrine by the lungs is compatible with a sodium dependent, carrier mediated transport, but several differences appear to exist between the transport and the site of uptake of norepinephrine and 5-hydroxytryptamine.