Resistance to the normal action of insulin contributes to the pathogenesis of a number of common human disorders, Type II (non-insulin-dependent) diabetes mellitus. This review is focused on current understanding of the molecular mechanisms regulating insulin action and the factors contributing to insulin resistance in skeletal muscle. Since skeletal muscle is considered the major organ responsible for glucose uptake under insulin-stimulated conditions, defects in this target tissue are likely to contribute to metabolic disregulation in Type II diabetes mellitus. Defects in insulin signal transduction through the insulin-receptor substrate-1/phosphatidylinositol 3-kinase pathway is associated with reduced insulin-stimulated glucose transport activity in skeletal muscle from Type II diabetic patients. Glucose transport, the rate limiting step in glucose metabolism, is mediated by glucose transporter 4 (GLUT4) translocation and can be activated in skeletal muscle by two separate and distinct signaling pathways; one stimulated by insulin and the second by muscle contractions. Level of physical exercise has been linked to improved glucose homeostasis and enhanced insulin sensitivity. Understanding the molecular mechanism for the activation of signal transduction pathways by which insulin and muscle contraction increase glucose transport will provide a link to defining new strategies to enhance glucose metabolism in the diabetic patient.