The relationship between low concentrations of high density lipoprotein cholesterol (HDL-C) and heightened risk for cardiovascular (CV) disease has been known for decades. Despite the consistent inverse relationship among epidemiological studies, the linkage between a residual low HDL-C among patients treated with statins and excess cardiovascular risk is less clearly established. Encouraging results from trials using niacin over the past 40 years have not been validated among more recent trials in patients taking contemporary anti-atherosclerotic therapy. Emerging evidence suggests that certain subsets of HDL particles may be more protective and/or more closely associated with CV disease than others, which may impact therapeutic benefits. Ongoing clinical trials will clarify whether raising HDL-C per se directly translates into a reduction in hard CV events. Until those results are available, the clinician is left with only weak evidence to support whether or not to target treatment of HDL-C with pharmacological therapy.