Isolevuglandins (isoLGs) are extremely reactive gamma-ketoaldehydes that avidly bind covalently with proteins and cause protein-protein as well as DNA-protein crosslinking. IsoLG-protein adducts are generated upon oxidation of low-density lipoprotein (LDL), and may contribute to atherogenesis since such adducts cause recognition and endocytosis of the modified LDL by macrophage cells. Levels of isoLG-protein adducts in human blood plasma are more closely correlated with disease than are the classical risk factors LDL or total cholesterol. We review the basic research that eventuated in the discovery of isoLGs and describe what is known about their natural occurrence and close connection with cardiovascular disease.