Manipulating the action of the Cholesteryl Ester Transfer Protein -CETP- and transforming the human lipid phenotype into one resembling the mouse lipid phenotype, in order to reduce susceptibility to atherosclerosis, is a hy- pothesis based on at least three lines of scientific evidence summarized within the introduction of this article. The follow- ing aspects related to the pharmacological manipulation of the CETP are discussed within the present article: a) CETP as a controversial protein involved in heterotypic and homotypic transport of neutral lipids between different lipoproteins; b) CETP as a protein involved in atherogenic dyslipidemia associated with the insulin resistance syndrome and c) pharma- cological manipulation of the CETP by using "second generation" drugs -dalcetrapib, anacetrapib and evacetrapib- focus- ing on the results of Phase IIb and Phase III studies published up to May 2012 . The article concludes with a review of the strengths, weaknesses, opportunities and current controversy on the HDL-centric versus LDL-centric theories.