The concentration of plasma low-density lipoprotein cholesterol (LDL-C) is reduced, while that of total high-density lipoprotein cholesterol (HDL-C) is increased, following inhibition of cholesteryl ester transfer protein (CETP). This combined effect has made inhibition of CETP an attractive pharmacological approach for reducing the residual incidence of cardiovascular disease (CVD) remaining after optimal LDL-lowering therapy. However, since HDLs represent a complex dynamic heterogeneous family of particles varying in size, composition and function, the concept is not without difficulties. CVD has been shown to alter the particle complexity, in terms of both relative abundance of size/density and composition. The effects of raising the plasma concentration of HDL-C on a background of ‘disease modified’ are largely unknown. Randomised clinical trials to date have failed to provide evidence of benefit for this approach. The CETP inhibitor, dalcetrapib, which showed no harmful effect, also had no ability to reduce LDL-C and the study may be considered as providing strong evidence that HDL raising per se is not an effective approach in reducing CVD. The remaining members of the CETP inhibitor family, currently in Phase III studies, are able to reduce plasma LDL-C and may, thus, provide a beneficial effect on CVD, as long as it is not reduced through the adverse effects of raising plasma HDL-C, which may well be dysfunctional. Subsequent analysis of these large randomised controlled trials, due to be published in 2016/17, may allow us to further understand the effect of CVD on the complex metabolism of HDL-C.