Background: The identification and characterization of monogenic obesity syndromes have improved our understanding of the inherited component of severe obesity and have had undoubted medical benefits. This knowledge has also helped to dispel the notion that obesity represents an individual defect in behaviour with no biological basis. Conclusions: For individuals at highest risk for complications of severe obesity, such findings provide a starting point for providing more rational mechanism-based therapies, as has successfully been achieved for congenital leptin deficiency.