Life expectancy in the developed world is increasing, but this comes with a simultaneous explosion in ‘agerelated’ as well as ‘lifestyle-related’ diseases, resulting in a decline in quality of life. Three such diseases are Type 2 diabetes mellitus (T2DM), Polycystic Ovarian Syndrome (PCOS) and non-alcoholic fatty liver disease (NAFLD), which all share a common reduced cellular response to the hormone insulin (termed insulin resistance). In T2DM, insulin resistance is clearly a contributing factor to disease progression, and is associated with obesity, the single greatest risk factor for all three conditions. Current research is focused on identifying the initial molecular lesion that results in reduced sensitivity to insulin, as improving insulin sensitivity would be beneficial to the prognosis of these conditions. However, the bulk of evidence suggests that more than one molecular defect in the insulin signalling pathway can lead to an insulin resistant phenotype. This raises the possibility that individuals with the same clinical phenotype may have distinct molecular reasons for the presence of the syndrome, and that the specific lesion influences the rate and direction of progression to the associated disease. Clearly the same insulin sensitiser could be of equal benefit in each disorder, if it reversed multiple signalling problems, however we suggest that appropriate molecular diagnosis of the defect may lead to a more targeted and effective therapeutic approach. This review discusses the molecular pathology of insulin resistance in relation to T2DM, PCOS and NASH. We highlight the shortcomings of current therapies, and suggest potential novel drug targets for each disorder.