Thermogenic combinations of ephedrine with caffeine and newer selective beta 3-agonists are being assessed for the treatment of obesity. The actions of beta-agonists may be multifaceted, with acute stimulation of thermogenic mechanisms in various tissues. During chronic treatment recruitment of brown fat may occur and hypertrophy of skeletal muscle may occur and simultaneously increase lean body tissue and reduce fat mass by stimulation of lipolysis and energy expenditure. The weight-reducing effect of an ephedrine-caffeine combination was superior to placebo treatment during 24 wk of energy restriction in obese women, whereas caffeine and ephedrine separately had no effect. In a second study it was found that ephedrine-caffeine compared with placebo preserved fat-free mass and enhanced fat loss, which could be accounted for both by anorexia (75%) and by increased thermogenesis (25%). The ephedrine-caffeine compound seems useful for the treatment of obesity and may serve as reference in the clinical assessment of new beta-agonists.