The metabolic syndrome represents a constellation of co-morbidities that include central adiposity, insulin resistance, dyslipidemia and hypertension, which results from an elevated prevalence of obesity. An increased abdominal adiposity is observed in upperbody obesity with preferential accumulation of fat in the visceral depot, which renders these individuals more prone to metabolic and cardiovascular problems. The pathophysiology of the metabolic syndrome seems to be closely associated to an elevated efflux of free fatty acids from the visceral fat compartment and a dysregulation of the expression of adipose tissue-derived factors (also termed “adipokines”). Weight reduction and increased physical activity represent the main approach to tackle the “diabesity” epidemic. Nonetheless, taking advantage of the different biochemical and molecular characteristics of visceral and subcutaneous adipose tissue may open up novel pharmacological strategies to combat the metabolic and cardiovascular derangements accompanying the metabolic syndrome.