The epidermal growth factor receptor (EGFR) is expressed in numerous cell types in the adult mammalian kidney and is activated by a family of EGF-like ligands. EGFR activation has been implicated in a variety of physiologic and pathophysiologic functions. There is increasing evidence that aberrant EGFR activation is a mediator of progressive kidney injury in diabetic kidney disease. This review will highlight recent studies indicating its potential role and mechanisms of injury of both glomerular and tubular cells in development and progression of diabetic kidney disease.