Despite tremendous progress made in the management of CHD, a significant number of fatal and nonfatal CHD events still occur, which leads researchers to target other modifiable risk factors for CHD including low HDL-c (high density lipoprotein cholesterol). Although the torcetrapib experience was a major blow to CETP inhibition and indeed to the entire field of HDL-targeted therapeutics, it was not fatal. The off-target effects of torcetrapib appear to be substantial and may have overridden any potential cardiovascular benefit. Despite continued uncertainty regarding the cardiovascular implications of genetic CETP deficiency and pharmacologic CETP inhibition, there remain reasons to believe in the mechanism and the possibility that clean CETP inhibitors will not only improve plasma lipids but also reduce cardiovascular risk.