<p>High-density lipoprotein cholesterol (HDL-C) has been inversely associated with atherosclerotic cardiovascular disease (ASCVD) risk. This relationship is the foundation of the “HDL hypothesis,” which states that increasing plasma HDL-C levels would result in a decrease in cardiovascular events. The recent surge in clinical testing of cholesteryl ester transfer protein (CETP) inhibitors provides valuable data for this hypothesis. The CETP inhibitors increase plasma HDL-C along with variable effects on low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB). The clinical outcomes of randomized controlled trials were heterogeneous, with several studies showing either neutral or adverse clinical outcomes despite robust increases in HDL-C values. These observations along with Mendelian randomization studies suggest that low HDL-C is a risk marker, not a causal mediator of ASCVD. New evidence points to HDL functionality, specifically cholesterol efflux potential and particle composition, instead of HDL-C concentration as a more relevant determinant of ASCVD risk. The favorable clinical outcomes observed with certain CETP inhibitors are more consistently explained by reductions in apoB-containing lipoproteins (including LDL-C and non-HDL-C), rather than increases in HDL-C itself. This distinction reframes the HDL hypothesis where HDL-C is merely a biomarker of ASCVD while apoB-containing lipoproteins are the more plausible causal treatment pathway. These findings have shifted the focus of the HDL hypothesis from the “quantity” to the “quality” of HDL.</p>