Our understanding of how insulin regulates carbohydrate, lipid and protein metabolism is relatively sophisticated. As to how impairments in these processes contribute to insulin resistance and other features of the metabolic syndrome remains unclear. The challenge is in defining how metabolism interacts with protein networks in specific tissues and what influence genetics and environment plays in modulating this homeostasis. We have been endeavouring to examine protein networks in different metabolic tissues from mice of discrete genetic backgrounds exposed to different diets and then integrating this information with human data to determine points of overlap. These approaches are beginning to unravel key features of metabolic networks that are associated with insulin resistance thus providing new avenues for therapeutic interventions.