Insulin resistance can be triggered by a range of perturbations including diet, obesity, inflammation or steroids. Thus, it is important to establish if there are convergent mechanisms that explain each of these modes or if insulin resistance is a multifactorial defect. One common aspect of most models is that insulin resistance is highly selective for a subset of insulin responsive pathways in fat, muscle and liver. Most notably, insulin resistance affects glucose metabolism while insulin regulation of lipid and protein metabolism may remain intact. This is consistent with the fact that insulin resistance does not stem from a defect in proximal elements of the insulin signalling network. Several labs including our own have established that a common feature of many insulin resistance models is increased oxidant production in mitochondria and this somehow leads to impaired glucose metabolism. To identify mechanisms that might contribute to this effect we recently used unbiased proteomic analysis in insulin resistant adipocytes and identified reduced levels of enzymes in the CoQ biosynthesis pathway combined with lower levels of CoQ in mitochondria as a common feature of insulin resistance. We propose that impaired CoQ function results in increased production of oxidants via Complex II leading to selective insulin resistance. This model has important implications for substrate switching in metabolic tissues and metabolic flexibility.