Atherosclerotic cardiovascular disease continues to be a major healthcare problem in developed as well as developing nations. Although adoption of a healthy lifestyle coupled with use of lipid modifying and antithrombotic agents significantly reduces the risk of major cardiovascular events, a significant residual burden remains. HDL based therapies have been suggested as potential ways to address this residual burden of disease in view of the known inverse relationship of HDL cholesterol and cardiovascular disease as well as a wealth of preclinical data and biological actions of HDL and its proteins. CETP, a key enzyme in HDL metabolism has emerged as a potential target since reduced CETP activity is associated with elevated levels of HDL cholesterol. However recent studies of failure of the ist CETP inhibitor, Torcetrapib, in a clinical trial has raised important questions regarding the value of HDL cholesterol as a biomarker for atheroprotective interventions. This brief review highlights recent developments in HDL biology with a special emphasis on the pros and cons of CETP inhibition as a therapeutic strategy for atherosclerosis.