Skeletal muscle constitutes the largest insulin-sensitive tissue in the body and is the primary site for insulin-stimulated glucose utilization. Skeletal muscle resistance to insulin is fundamental to the metabolic dysregulation associated with obesity and physical inactivity, and contributes to the development of the metabolic syndrome (MS). The inability to efficiently take up and store fuel, and to transition from fat to glucose as the primary source of fuel during times of caloric abundance (high insulin) or scarcity (low insulin) has been termed metabolic inflexibility which contributes to a whole body metabolic dysregulation and cardiovascular risk. Potential mechanisms contributing to reduced insulin signaling and action in skeletal muscle includes adipose tissue expansion and increased inflammatory adipokines, increased renin-angiotensin-aldosterone system (RAAS) activity, decreases in muscle mitochondrial oxidative capacity, increased intramuscular lipid accumulation, and increased reactive oxygen species. Future research is focused upon understanding these and other potential mechanisms in order to identify therapeutic targets for reducing MS risk. Strategies will include adequate physical activity and maintaining a healthy weight, but may also require specific pharmacologic interventions.