Pathogenesis of atherosclerosis and the search for novel therapies and diagnostic markers remain major problems of modern medicine. Currently available therapeutic approaches are often not sufficiently effective, probably due to the complexity of the disease mechanisms. This review focuses on the evaluation of low density lipoprotein (LDL) and high density lipoprotein (HDL) as risk factors of atherosclerosis. We summarize the current paradigm of LDL involvement in atherogenesis and HDL presumably protective properties. We next discuss the available evidence for the protective effect of HDL and the consequences of HDL dysfunction. Finally, we question the currently widely accepted hypothesis of the central role of oxidized LDL in atherogenesis and present an alternative concept of multiple modification of LDL that confers its pro-atherogenic properties.