The formation of lipid-loaded macrophages, lipidotic cells with irreversible accumulation of undigested modified low-density lipoproteins in lysosomes, is a key event in atherogenesis. Here, Otília Vieira from CEDOC, Portugal desribes how cholesteryl hemiesters - a family of lipids that are at high concentrations in cardiovascular disease patients - cause irreversible lysosome defects in macrophages. She further describes how these dysfunctional lysosomes are more prone to fuse with the plasma membrane, and secrete their undigested luminal content. This could be a novel mechanism that may be important in the pathogenesis of atherosclerosis.