The characterization of genetic and experimental syndromes of obesity in rodents has played a major role in the identification of the molecular components of energy homeostasis over the last 15 years (Friedman, 2004). The finding that mutations in many of these genes result in severe obesity in humans has demonstrated that these pathways, in particular the leptin-melanocortin pathway, are highly conserved across mammalian species. There are a number of human genetic syndromes where obesity occurs in association with developmental delay and organ-specific abnormalities. In many cases, significant progress has been made in understanding the molecular and cellular mechanisms underlying these complex syndromes (for example in Bardet-Biedl Syndrome), but the mechanisms whereby mutations in these specific genes lead to obesity are only beginning to emerge.