Metabolic syndrome (MetS) can be considered a pheno-physiological cluster of metabolically interrelated risk factors for diabetes mellitus and cardiovascular disease. MetS has emerged as a result of complex interactions among environmental stresses and MetS gene networks and their products. In this review we summarize trends in MetS definitions, their associated controversies and possibilities for their refinement. The National Cholesterol Education Program MetS definition with its improvements by the American Heart Association and NHLBI Conference has the potential to become the primary clinical definition of MetS. For the first time, by reviewing a large body of literature, we construct MetS gene networks in humans and in rodents. These MetS gene networks can serve as a budding platform to develop new hypotheses regarding the genetic mechanisms underlying MetS. We also extend the notion of MetS to mouse models. New and improved molecular genomics and proteomic tools have been developed in parallel with the MetS epidemic which in conjunction with improved and novel computational statistical methods have magnified the genetic resolution of MetS analyses. Our results justify the existence of MetS as a meaningful syndrome and suggest that a better understanding of its etiology can benefit the health of human kind.