The increasing prevalence of obesity in the United States is widely recognized as a complex problem with significant public health implications, morbidity, mortality, and costs. Pharmacotherapy can contribute to the treatment of obesity. The regulation of appetite and body weight involves multiple parallel neuronal and bodily mechanisms. Not surprisingly, experience has shown that a medication that targets any one mechanism produces weight loss of 5%-10%. Although weight loss of this magnitude may produce significant reductions in risk factors associated with cardiovascular morbidity and mortality, patients expect cosmetically meaningful reductions in weight (~20%-25%). Combining 2 medications that work via different mechanisms, that is, "combination pharmacotherapy," is an approach to obtaining cosmetically relevant reductions in weight. The most effective example of this approach was the combination of phentermine and fenfluramine. This article will describe a novel combination pharmacotherapy developed in clinical practice: the combination of phentermine with the serotonin precursor L-5-hydroxytryptophan plus the peripheral decarboxylase inhibitor, carbidopa. Observational data on the efficacy and safety of this combination pharmacotherapy will be presented. In conclusion, combination pharmacotherapy can make important contributions to the treatment of obesity. Controlled clinical trials should be done before such combination treatments are widely adopted.