Insulin is the principal hormone of metabolic regulation. Reduced responses to insulin constitute an underlying feature of type 2 diabetes. It is, therefore, incumbent on those who work in this area (as well as many others) to characterize this response, in as simple and consistent a way as possible, so that this measure can be used both in the investigational and clinical setting. This type of approach, although eminently useful, is necessarily an oversimplification. Not only does insulin sensitivity change in pathological situations, but also in normal physiology. Tissue-specific, metabolite-specific, as well as process-specific responses may be expected to occur. Variations also occur in time-depending on the physiological state of the individual (e.g. pregnancy, aging) or following diurnal rhythms. It is perhaps remarkable that any consistent assessment of overall insulin sensitivity can be made. The observation that this can often be achieved has led to hypotheses suggesting that sensitivity to insulin is primarily determined at a single site (tissue, metabolite). At the same time, there are many discussions about the inconsistencies inherent in different approaches to the measurement of this parameter, suggesting that some of these variants, metabolic or otherwise, could lead to the low correlation between methods sometimes seen. Nevertheless, most methods used in the assessment of insulin sensitivity examine the response to insulin of a single metabolite, glucose, primarily in the muscle and liver, and under fasting conditions and should, therefore, demonstrate insulin sensitivity that is comparable among methods.