There is only one well-established relationship between blood cholesterol lipid fractions and coronary artery disease (CAD) that meets all the Heiss and Tyroler criteria of causality. While there are a number of blood lipid fractions, only LDL cholesterol satisfies these criteria. We review the effect of reducing low density lipo-protein (LDL) cholesterol levels on CAD in the landmark lipid intervention trials performed since 1972. Lowering of LDL cholesterol consistently and systematically resulted in a reduction of cardiovascular events, irrespective of the therapy applied or the changes in high density lipoprotein (HDL) cholesterol or triglyceride levels. Findings accumulated over many studies and many years provided sufficient evidence to satisfy all the criteria required to establish a causative relationship between LDL cholesterol and CAD. Consistent inter-ventional benefit demonstrated that reduction of LDL cholesterol is currently the treatment of choice in prevention of heart disease.