The incidence of type 2 diabetes mellitus (T2D) and obesity is increasing rapidly worldwide, reaching epidemic proportions. Insulin resistance is a key feature in both conditions and plays an important pathophysiological role. Over the last two decades a central role in the origin of insulin resistance has emerged for defects in the intracellular insulin signaling cascade leading to glucose uptake. Herein, we will 1) review insulin signaling pathways leading to glucose uptake, 2) review mouse models of insulin resistance that demonstrate the pathophysiologic importance of specific defects of these pathways and 3) discuss the molecular basis for insulin resistance in some human disease states known to be associated with insulin resistance. Finally, we will briefly mention some novel treatment targets for T2D stemming from this knowledge.