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Megalin is a member of the low-density lipoprotein receptor superfamily. It has been recognized as an endocytic receptor for a large spectrum of ligands. As a consequence, megalin regulates homeostasis of many molecules and affects multiple physiological and pathophysiological functions. The renin-angiotensin system is a hormonal system. A number of studies have reported contributions of the renin-angiotensin system to atherosclerosis. There is evolving evidence that megalin is a regulator of the renin-angiotensin system, and contributes to atherosclerosis. This brief review provides contemporary insights into effects of megalin on renal functions, the renin-angiotensin system, and atherosclerosis.