Skeletal muscle is the primary site of insulin-mediated glucose uptake and defects in this insulin target tissue precede the manifestation of Type 2 diabetes. Our central hypothesis is that alterations in insulin signal transduction to glucose transport in skeletal muscle impair whole body glucose homeostasis and contribute to Type 2 diabetes pathogenesis. Research efforts are directed towards understanding the regulation of pathways governing glucose metabolism. The current view of insulin signaling and therapeutic targets to enhance insulin action in skeletal muscle will be presented in this symposium lecture. Physical exercise/muscle contraction elicits an insulin-independent increase in glucose transport and perturbation of this pathway may bypass defective insulin signaling. The exercise-responsive signaling molecules governing glucose metabolism in skeletal muscle are largely unknown. AMP-activated protein kinase (AMPK) is an 'exercise-responsive' signaling molecule that is involved in glucose homeostasis and has been heavily explored as a pharmacological target for the treatment of Type 2 diabetes. This lecture will also highlight the current understanding of the AMPK in the control of skeletal muscle metabolism. Elucidation of the pathways governing insulin action is essential to gain insight into Type 2 diabetes causation and also to identify potential biochemical entry points for pharmaceutical intervention. This goal may be accomplished through integrating clinical approaches designed to identify the cause of insulin resistance in humans, experimental approaches to biologically validate the identified targets, and pharmaceutical development to translate discovery into treatment and disease management.