Adiponectin encoded by the APMI gene is one of the adipocyte-expressed proteins that function in the homeostatic control of glucose, lipid, and energy metabolism. Its dysregulation has been suggested to be involved in disorders covering the metabolic X syndrome, such as insulin resistance, obesity, type 2 diabetes, and coronary artery disease. Recent data present evidence of a genetic modulation of the adiponectin level, and linkage of the 3q27 locus, where the APMI gene lies, with diabetes and features of the metabolic X syndrome playing a putative role of the APMI gene in this syndrome. In this article, we present an overview of the results available to date and discuss positive evidence for a role of genetic variants of the APMI gene and questions that genetic data raise.