The prevalence of metabolic diseases is taking on epidemic proportions and poses a serious threat to human health. Current treatment options have proven insufficient to cope with obesity and diabetes because they rarely restore normal metabolism and thus leave patients exposed to life-threatening complications. Successful management of these diseases depends on novel, improved therapeutic strategies targeting early intervention in disease progression. Discovery of novel metabolic disease targets has been hampered by the complexity of contributing environmental and genetic factors, as well as the need for potent but safe treatments suitable for chronic diseases. Genomic approaches are excellent tools to manage genetic complexity and have been applied successfully to identify candidate target genes that will lead to the development of novel therapies for metabolic diseases.