The insulin receptor substrates function at the heart of the insulin signalling network. It has recently become apparent that the intracellular localisation of these molecules is regulated in a precise manner that is critical for both the generation and the termination of the insulin signal. Some insulin receptor substrate isoforms appear to be associated with an insoluble matrix that resembles the cytoskeleton. When inappropriately dissociated from this matrix the signalling network collapses concomitant with loss of insulin sensitivity.