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To date, observational studies have repeatedly demonstrated an inverse association between HDL cholesterol (HDL-C) levels and cardiovascular outcomes. Although the efficacy of established HDL-modifying treatment strategies have been examined in multiple large-scale phase III trials, findings from these experimental studies conflict with the hypothesis that HDL-C levels are atheroprotective. In this review, we describe the trial evidence to date, and attempt to place these results in the broader context of recent hypotheses for the association between HDL-C levels and clinical outcomes.Both translational and genetic studies are in line with the hypothesis that HDL-C levels do not hold causal importance for cardiovascular risk reduction. In addition to its possible role as a biomarker for other atherogenic lipoproteins, efforts should be made to elucidate HDLs’ role in lipoprotein flux, which is increasingly being linked to surrogate outcomes of importance to cardiovascular epidemiology. In the future, it will be of great importance to link this measure of HDL functionality to clinical endpoints.Although trial evidence does not support an atheroprotective role of overall HDL-C plasma levels, HDL function/lipoprotein flux holds great promise for the development of novel therapeutic approaches.