Focal glomerulosclerosis (FGS) is commonly seen in human and in experimental models of chronic renal disease. Although considerable experimental data suggest that hypertension is important in progressive nephron damage, recent studies also have indicated that abnormal lipid metabolism may be an independent risk factor in the pathogenesis of FGS. Indeed, the synergistic impact of hypertension and hyperlipidemia in the pathogenesis of FGS may be analogous to the role of these factors in the pathogenesis of atherosclerosis. This review focuses on some of the recent and pertinent data that support a role of lipid-mediated glomerular injury in the pathogenesis of progressive renal disease.