The lipid-mobilizing and thermogenic effects of several alpha 2 antagonists were explored. Studies were undertaken in humans and in the dog, which possess fat-cell alpha 2-adrenergic receptors (alpha 2-AR) and beta-adrenergic receptors (beta-AR) that are very similar. Yohimbine (alpha 2-AR antagonist) was used in humans whereas other recent alpha 2 antagonists were used in dogs. Oral yohimbine (0.2 mg/kg) promoted a lasting increment of plasma nonesterified fatty acids (NEFAs) and noradrenaline concentrations without significant action on cardiovascular parameters or insulin secretion. In dogs, a direct correlation between the variations of plasma NEFA and noradrenaline concentrations induced by alpha 2 antagonists (1.2 mmol/kg iv) was observed; a result supporting the relationship between lipolysis and the pharmacologic activation of the sympathetic nervous system. Cardiovascular effects were almost absent whereas a long-lasting thermogenic effect was observed. The lipid-mobilizing effect of alpha 2 antagonists is mainly attributable to the increase in synaptic noradrenaline. The potential interest of alpha 2 antagonists in diet therapy is discussed.