Diabetic nephropathy (DN) is a microvascular complication of diabetes that is characterized by proteinuria, glomerulosclerosis, and decreased kidney function ultimately leading to end stage renal disease; in fact, DN is the leading cause of end stage renal disease in the western world. Glycemic and blood pressure control are currently the most common forms of prevention and treatment of the disease. However, despite good glycemic and blood pressure control, many patients still progress to end stage renal disease and require renal replacement therapy, leaving investigators searching for novel DN therapy targets. The AMP-activated protein kinase (AMPK) is a heterotrimeric protein that serves as an energy regulator for the cell. However, numerous extracellular factors that contribute to DN progression (including glucose, vascular endothelial growth factor, insulin, and AngII) may inhibit AMPK activity. Two recent studies indicate that AMPK activity decreases during DN progression (Lee et al. Am J Physiol Renal Physiol 292(2):F617-27 and Cammisotto et al. Am J Physiol Renal Physiol. 294(4):F881-F889). In order to better understand the potential role that AMPK inhibition has in DN, we have reviewed the mechanisms of AMPK regulation, how these regulatory mechanisms are changed in DN, and what effect that might have on AMPK activity. Additionally, we discuss the downstream effects of AMPK signaling, and how diminished AMPK activity would affect these events. We hope that this review may stimulate future research into the beneficial effects of up-regulating AMPK in ameliorating DN.