Emerging evidence supports that the entity known as idiopathic nodular glomerulosclerosis is not idiopathic. A strong causative association with longstanding cigarette smoking and hypertension has been identified. Morphologically, smoking-associated nodular glomerulosclerosis closely resembles diabetic nephropathy. The potential roles of advanced glycation end products, oxidative stress, angiogenesis, and hemodynamic perturbations are explored.