Obesity results when the energy intake exceeds expenditure for a long period. The first law of thermodynamics, which describes this relationship, does not provide insight into the failures to couple energy intake and expenditure. Research over the past two decades has provided an unprecedented expansion of knowledge about the physiological and molecular mechanisms regulating body fat. Perhaps the greatest impact has resulted from the cloning of genes corresponding to the five mouse monogenic obesity syndromes and the subsequent characterization of the human counterparts to these syndromes. Extensive molecular and reverse genetic studies (mouse knockouts) have helped establish other critical pathways that regulate body fat and food intake, and also have either validated or refuted the importance of previously identified pathways.