The study of rodent monogenic models of obesity has yielded significant insights into the pathogenesis of obesity. Multiple independent mutations in several genes can produce obesity. As these genes act in different regulatory pathways, it is clear that multiple mechanisms can produce obesity. Furthermore, a single gene defect can produce regulatory deficits in multiple modes of energy expenditure. The most severe forms of genetic obesity involve multiple pathogenic processes. It is significant that regulatory defects in any single component of caloric intake or energy expenditure appear to be sufficient to produce obesity. Finally, the systems regulating energy balance are loosely coupled; positive and negative influences are not completely balanced, both in strength as well as temporally.