By the term "insulin resistance" we understand the attenuation of insulin-stimulated glucose uptake, which is mainly due to attenuated glycogen synthesis in skeletal muscle and is partially compensated with regard to plasma glucose homeostasis by hyperinsulinemia. Other mechanisms of insulin are either not attenuated or are less so and may contribute via hyperinsulinemia to the prevalence of hypertension, obesity, dyslipoproteinemia and type-II diabetes. At the level of insulin receptors, resistance can be due to muscle-specific, preferential expression of the low-affinity B-isoform of the insulin receptors. In rare cases of extreme resistance, it can also be due to several mutations at the insulin receptor gene or due to insulin-receptor autoantibodies. At the postreceptor level, the translocation and or expression of the insulin-responsive glucose carrier GluT-4 can be down-regulated via the hexosamine pathway by hyperglycemia plus hyperinsulinemia. Furthermore, Glut-4 can be inhibited and/or down-regulated by sustained insulin deficiency, partially via c-AMP-dependent pathways. Additionally, the insulin-induced glycogen synthesis in skeletal muscle can be attenuated by the endogenous peptides amylin and calcitonin-gene-related peptide, and by modulations of endothelial function, perfusion and capillary recruitment in the microcirculation of skeletal muscle. Epidemiological data indicate a genetic predisposition for insulin resistance. However, among the many mechanisms potentially contributing to the complex syndrome of insulin resistance, no specific localization of that predisposition can be proposed at present.