Although obesity is a chronic disease like hypertension and diabetes, obesity is not treated with drug combinations as are other chronic diseases. This is because orlistat and sibutramine, the two drugs approved for long-term treatment of obesity, do not result in additive weight loss when combined. This article discusses the history of combination drug therapy for treating obesity, the lessons learned from that experience, and describes the drug combinations now in development. One combination of two standardized dietary herbal supplements that result in clinically significant weight loss is also described. Obesity is poised to enter the era of combination drug therapy, as is now the routine in the treatment of other chronic diseases like hypertension and diabetes. The advent of combination drug therapy for obesity treatment offers hope for increasing the efficacy of obesity pharmacotherapy.