Glutathione peroxidase 1 (GPX1) is a selenium-dependent enzyme that reduces intracellular hydrogen peroxide and lipid peroxides. While past research explored regulations of gene expression and biochemical function of this selenoperoxidase, GPX1 has recently been implicated in the onset and development of chronic diseases. Clinical data have shown associations of human GPX1 gene variants with elevated risks of diabetes. Knockout and overexpression of Gpx1 in mice may induce types 1 and 2 diabetes-like phenotypes, respectively. This review assembles the latest advances in this new field of selenium biology, and attempts to postulate signal and molecular mechanisms mediating the role of GPX1 in glucose and lipid metabolism-related diseases. Potential therapies by harnessing the beneficial effects of this ubiquitous redox-modulating enzyme are briefly discussed.