Metabolic inflexibility of skeletal muscle, that is, the inability to acutely shift its reliance between lipids or glucose during fasting and postprandial conditions, is closely linked to the development of metabolic syndrome and cardiovascular risk and is increasingly considered to represent another component of myocyte insulin resistance, alongside decreased oxidative capacity as well as reduced anabolic-anticatabolic capacity. Potential contributive mechanisms include adipose tissue expansion, increased inflammatory adipokines, increased renin-angiotensin-aldosterone system (RAAS) activity, decreased mitochondrial oxidative capacity of muscles, increased intramuscular lipid accumulation, and increased reactive oxygen species. Understanding these and other mechanisms and identifying therapeutic targets along with specific pharmacological interventions for reducing metabolic syndrome risk will be the focus of future research.