High-density lipoprotein (HDL) metabolism is complex, and its role as a causal risk factor for cardiovascular disease (CVD) has evolved over the past several years. Low high-density lipoprotein cholesterol (HDL-C) levels are clearly an independent predictor of CVD. However, therapeutic interventions aimed at increasing plasma HDL-C (niacin and cholesterol ester transfer protein [CETP] inhibitors) have failed to show efficacy in outcome trials. Furthermore, human genetic variants associated with HDL-C levels have failed to support the causal role of HDL-C in the pathology of CVD while validating the causality of triglyceride-rich lipoproteins in the pathogenesis of atherosclerosis. Over the past decade, because of the genomic data and the failure of HDL-C-raising trials to reduce major adverse cardiac events or HDL infusions reducing atheroma volume determined by intravascular ultrasound, there has been a significant shift away from targeting HDL to reduce CVD toward lowering triglyceride as the preferred option to mitigate residual atherogenic risk. Because there is no doubt that low HDL-C is a sensitive biomarker for CVD, there has been an effort to better understand how measurements of the complex nature of HDL subspecies or functionality can be clinically useful to either better assess cardiovascular (CV) risk or identify therapies that promote atherosclerotic regression.