A discrete, ascending fiber system that supplies the hypothalamus with most of its noradrenergic terminals was destroyed at midbrain level, both electrolytically and with local injections of 6-hydroxydopamine, a destructive agent specific for catecholaminergic neurons. The result was hyperphagia leading to obesity. Fluorescence histochemical analysis showed that loss of noradrenergic terminals in ventral bundle termination areas such as the hypothalamus was necessary for hyperphagia. Damage to dorsal bundle or dopaminergic projections was not. Prior treatment with desmethylimipramine to selectively block uptake of 6-hydroxydopamine into noradrenergic neurons prevented both hyperphagia and loss of norepinephrine fluorescence. The lesions that produced hyperphagia also reduced the potency of d-amphetamine as an appetite suppressant. It is concluded that this noradrenergic bundle normally mediates suppression of feeding, thereby influences body weight, and serves as a substrate for d-amphetamine-induced loss of appetite.