Alterations and injury to glomerular podocytes play a key role in the initiation and progression of diabetic kidney disease (DKD). Multiple factors in diabetes cause abnormalities in podocyte signaling that lead to podocyte foot process effacement, hypertrophy, detachment, loss, and death. Alterations in insulin action and mammalian target of rapamycin activation have been well documented to lead to pathology. Reduced insulin action directly leads to albuminuria, increased glomerular matrix accumulation, thickening of the glomerular basement membrane, podocyte apoptosis, and glomerulosclerosis. In addition, podocytes generate factors that alter signaling in other glomerular cells. Prominent among these is vascular endothelial growth factor-A, which maintains glomerular endothelium viability but causes endothelial cell pathology when generated at too high a level. Finally, circulating vascular factors (eg, activated protein C) have a profound effect on podocyte stability and survival. This cytoprotective factor is critical for podocyte health, and its deficiency promotes podocyte injury and apoptosis. Thus, the podocyte sits in the center of a network of paracrine and hormonal signaling systems that in health keep the podocyte adaptable and viable, but in diabetes they can lead to pathologic changes, detachment, and death.