Metformin has been used for nearly a century and is now the most widely prescribed oral anti-diabetic agent worldwide. Yet how metformin acts remains only partially understood and controversial. One key reason may be that almost all previous studies were conducted with supra-pharmacological concentrations (doses) of metformin, 10–100 times higher than maximally achievable therapeutic concentrations found in patients with type 2 diabetes mellitus. Metformin is a first-line agent for treating patients with type 2 diabetes mellitus; however, its mechanism of action remains controversial. In this Essay, He and Wondisford discuss proposed mechanisms and raise awareness that studies employing supra-physiologic concentrations (doses) of metformin should be interpreted with caution.