Complex interactions between inherited factors and the environment determine an individual’s susceptibility to type 2 diabetes mellitus and related syndromes. Insulin resistance, obesity, hypertension, and hyperlipidemia frequently precede the development of frank diabetes and aggregate in families. Several genome-wide scans have recently been performed in families with this constellation of findings, called the “metabolic syndrome.” These analyses strongly support an inherited component to the syndrome. In this review, we provide an overview of the evidence in support of an inherited contribution to the metabolic syndrome and the search for causative genomic regions. When multiple genome scans involving different patient cohorts implicate a common genomic region as susceptible to the metabolic syndrome, it is highly likely that causative genes reside in that area. Identification of these genes will dramatically improve our understanding of the mechanisms that underlie the metabolic syndrome, and could lead to novel treatment strategies. It is hoped that these therapies will also prevent the future development of type 2 diabetes mellitus and atherosclerotic complications, both common among individuals affected by the metabolic syndrome.