MS encompasses a constellation of cardiovascular risk factors, and is a common, age-related disorder mainly driven by the increasing prevalence of obesity and it has been claimed to be a powerful predictor of cardiovascular disease. However, the existence of such a syndrome has been recently challenged on the basis of uncertainty of the pathogenetic mechanism(s), too many definitions and diagnostic criteria, doubt about any advantage as compared to existing risk calculation engines. Insulin resistance has been postulated to represent the common denominator of MS. In spite of the fact that insulin resistance is generally defined as the impaired ability of insulin to promote glucose utilization in insulin-dependent tissues, recent work has provided the basis for understanding how impaired insulin signalling activation and concomitant hyperinsulinemia may trigger, in tissues such as the endothelium, pathways involved in the atherogenic process as well as inflammation. Nonetheless, insulin resistance is unlikely to be the unique pathogenetic mechanism since only a percent of individuals with MS have impaired insulin sensitivity, whereas not all the insulin-resistant subjects have MS. This is reflected also in the frequent use of diagnostic criteria not necessarily including measurements of insulin action. However, the advantage of a definition also relies in its practicability. From this point of view it appears that individuals meeting the ATPIII criteria, often have other abnormalities that may contribute to cardiovascular risk. To which extent MS may perform better than other risk calculators remain a matter of discussion. However, it is apparent that such risk calculation would be improved by considering separately specific conditions, for instance diabetic vs. non-diabetic patients. Finally, when different therapeutic approaches toward one or the other component of the syndrome are considered it becomes clear how difficult it is to affect the entire syndrome, strengthening the entangled interconnection of the features within the syndrome.