Leptin is a 16 kDa protein secreted by fat cells which regulates body weight and thermogenesis at sites within the brain. Blood-borne leptin reaches those brain sites because of a saturable transport system located at the blood-brain barrier (BBB). Impaired transport occurs in obese rodents and likely underlies the resistance to the actions of peripheral leptin seen in obesity. Here, we show that leptin transport into the brain is enhanced 2-3-fold by epinephrine and other agents which are more specific for the alpha1 adrenergic receptor. Epinephrine had no effect on the transport across the BBB of insulin or tumor necrosis factor, on BBB integrity, or on the size of the vascular space of the brain. Dopamine, acetylcholine, histamine, serotonin, thyroid hormones, and phentolamine were without effect. Of several amino acids tested, only the catecholamine precursor tyrosine had an effect on leptin transport. Epinephrine was effective after intravenous or intraperitoneal injection, but neither epinephrine nor any of the other monoamines given by intracerebroventricular injection had an effect on leptin transport. These results show that epinephrine likely acts at a site on the luminal surface of the BBB. In conclusion, epinephrine works at an alpha1-like adrenergic, luminal side to enhance the transport of leptin across the BBB.