Abstract: Insulin resistance is a characteristic feature of type II diabetes mellitus and obesity. Although defects in glucose homeostasis have been recognized for decades, the molecular mechanisms accounting for impaired whole body glucose uptake are still not fully understood. Skeletal muscle constitutes the largest insulin‐sensitive organ in humans; thus, insulin resistance in this tissue will have a major impact on whole body glucose homeostasis. Intense efforts are under way to define the molecular mechanisms that regulate glucose metabolism and gene expression in insulin‐sensitive tissues. Knowledge of the human genome sequence, used in concert with gene and/or protein array technology, will provide a powerful means to facilitate efforts in revealing molecular targets that regulate glucose homeostasis in type II diabetes mellitus. This will offer quicker ways forward to identifying gene expression profiles in insulin‐sensitive and insulin‐resistant human tissue. This review will present our current understanding of potential defects in insulin signal transduction pathways, with an emphasis on mechanisms regulating glucose transport in skeletal muscle from people with type II diabetes mellitus. Elucidation of the pathways involved in the regulation of glucose homeostasis will offer insight into the causation of insulin resistance and type II diabetes mellitus. Furthermore, this will identify biochemical entry points for drug intervention to improve glucose homeostasis.