BACKGROUND: Bupropion and naltrexone are centrally active drugs that have shown potential efficacy - alone and in combination - for the treatment of obesity. OBJECTIVE: To explore the efficacy and safety of naltrexone and bupropion alone and in a novel combination drug that utilizes sustained-release (SR) formulations of both drugs and to evaluate their efficacy in promoting weight loss. The mechanisms of action of these centrally acting drugs are discussed. Preclinical and clinical studies of bupropion and naltrexone alone and in combination are reviewed. RESULTS/CONCLUSIONS: Both bupropion and naltrexone have been shown individually to induce weight loss. Bupropion has greater efficacy as monotherapy. Naltrexone SR potentiates the effects of bupropion SR; thus, this synergistic combination has the potential for additional weight loss compared to monotherapy. Current Phase III trials will yield further safety and efficacy information regarding these drugs in combination.