The prevalence of obesity has increased in alarming proportions over the past 10 years and being recognized as an epidemic. Obesity is now considered as a disease, and is associated with insulin resistance. This follows a wide array of pathophysiological sequelae including type 2 diabetes, hypertension, hyperlipidemia, and atherosclerosis, collectively referred to as metabolic syndrome or syndrome X. The increased numbers of mortality and morbidity from obesity-related complications like diabetes and cardiovascular diseases have raised serious concern. Despite the growing understanding of biologic pathways underlying feeding behavior and metabolic disorders leading to weight gain and eventually obesity, a proportional success has not been achieved in terms of drug discovery to combat the obesity epidemic. Several approaches like appetite control, inhibition of dietary fat absorption, insulin and leptin revival, inhibition of fat synthesis, and increased fat mobilization and burning, have been known to develop therapies to treat obesity. These biologic pathways are carried out by a number of players in a tissue-specific manner. Recent studies using knockouts and transgenics have further identified and validated several molecular targets directly involved in the pathogenesis of obesity. However, despite the plethora of research data in the obesity arena and validated biologic targets, a blockbuster drug is yet to hit the market. This review discusses the importance of major tissues and proteins in the pathogenesis of obesity, and ways to combat obesity by modulating these players.