The multi-ligand Receptor for Advanced Glycation Endproducts (RAGE) is expressed in podocytes and endothelial cells in the human and murine glomerulus. Although present at low levels in homeostasis, RAGE expression is increased during disease. Pharmacological antagonism of RAGE or its genetic deletion imparts marked protection from podocyte effacement, albuminuria and glomerular sclerosis in disease models. In human subjects, associations between specific genetic polymorphisms of RAGE and levels of soluble forms of RAGE are linked to disease states in the kidney. In this review, we summarize the evidence from mouse to man, linking RAGE to the pathogenesis of nephropathy.