Although the relationship between HDL (high density lipoprotein) function and cardiovascular (CV) risk has been extensively explored, the premise that HDL elevation is linked to reduced CV risks and that high HDL cholesterol (HDL-C) might be a potential surrogate biomarker for reduced CV risk remains controversial. Substantial genetic, molecular, biochemical and preclinical evidence have raised the hope that HDL-C elevation via CETP inhibition might generate clinical benefits. However, four large-scale clinical trials with the CETP inhibitor torcetrapib failed to demonstrate benefits on CV clinical outcomes. Likewise, biomarkers that were supposed to predict vascular risk reduction provided disappointing results. The sad tale of torcetrapib development emphasizes the need for a paradigm shift from the conventional drug development mode to a biomarker-based Translational Medicine (TMed) strategy. Emergence of further CETP inhibitors encourage continued development of such compounds for cardiovascular risk management. However, there is a need to adopt biomarker-driven TMed strategies in target validation, target-compound interaction, pharmacodynamic activities, disease modification and patient selection to guide future drug development efforts. This commentary analyzes the issues surrounding the demise of torcetrapib and proposes a TMed-based road map towards successful development of new CETP inhibitors.