The pivotal role of the sympathoadrenal system in the defense of le milieu interieur has, in the last 15 years, been extended to include the fat stores-a notion that forms the basis of current strategies for thermogenic stimulation in obesity therapy. The search for effective and safe sympathetic stimulants has been directed at two main levels: (i) the development of novel beta-agonists selective for thermogenesis, and (ii) the evaluation of drugs already in clinical use for other purposes (e.g. ephedrine) which could conceivably increase the release of catecholamines to levels that enhance thermogenesis without significant cardiovascular effects. A re-direction of these strategies seem inevitable because at therapeutic doses, the thermogenic effects of these sympathomimetics seem to be considerably dampened by negative feedback mechanisms that operate both extracellularly (e.g. via adenosine & prostaglandins) as well as inside the cells (via cAMP phosphodiesterases). Such a contention is supported by studies both in man and in animals showing that methylxanthines and aspirin, drugs known to be capable of interfering with these modulators, potentiate the thermogenic effects of ephedrine. Future research aimed at clarifying the types and subtypes of these negative modulators of sympathomimetic-induced thermogenesis and their targeting by more selective antagonists would no doubt be pivotal in providing the safe drug combination with the necessary thermogenic properties to assist the management of obesity.