We have been using both inbred and outbred mouse strains to probe the underlying architecture of whole-body insulin resistance and metabolic dysfunction. This has revealed new insights into phenotypic relationships and their underlying causality. For example, despite enormous variance in adiposity in chow fed mice very few exhibit hepatic steatosis indicating that diet plays an essential role in NASH. One of the surprising findings has been the strong relationship between glycolytic capacity in muscle and insulin sensitivity. These kinds of relationships and the general road map for how such mouse models might be used in going forward will be discussed.