We have utilized global unbiased phosphoproteomic analysis of insulin responsive tissues to construct a large scale map of the insulin regulated signaling network. This has revealed key regulatory nodes together with novel substrates of major insulin regulated kinases such as Akt. Using machine learning we have discovered several new Akt substrates that have revealed novel aspects of insulin action, several of which will be discussed. We have also applied similar approaches to examine changes in insulin signaling and the total proteome in adipocytes rendered insulin resistant using a range of physiological perturbations. These studies have revealed novel insights into the mechanism of insulin resistance, which appears to involve the induction of an insulin sensitive pathway in adipocytes that impairs insulin regulated glucose metabolism.