The first large population-based study to show an inverse relationship between circulating HDL-cholesterol (HDL-C) concentrations and coronary heart disease (CHD) was a cross-sectional analysis of men of Japanese ancestry living in Hawaii (1). Four prospective epidemiological studies extended these finding showing that a 1mg/dL increase in HDL-C was associated with a 2% decrease in CHD in men and a 3% decrease in CHD in women (2). The inverse relationship was independent of age, smoking, low density lipoprotein cholesterol (LDL-C), blood pressure, and body mass index (BMI), but was attenuated by adjustment for non-HDL-C (ie, VLDL+ LDL-C) concentrations. These findings suggested that raising HDL-C could be therapeutically beneficial but were insufficient to completely disentangle the close relationship between HDL and triglyceriderich lipoproteins. The subsequent failure of most clinical trials aimed at raising HDL-C concentrations, especially the trials conducted with cholesteryl ester transfer protein (CETP) inhibitors, as well as detailed studies of the genetic factors underlying HDL-C variation have called into question the causal relationship between HDL-C and CHD, and have refuted the idea that raising HDLC would automatically have therapeutic benefit. Nonetheless, HDL-C remains an important CHD risk factor that appears in American Heart Association and European Atherosclerosis Society guidelines to estimate risk and guide treatment. HDL-C measurements may integrate the effects of multiple risk factors including obesity, insulin resistance and hypertension. Moreover, an abundance of evidence indicates that the ability of HDL to mediate cholesterol efflux from macrophage foam cells does associate with protection from atherosclerosis, holding promise for future therapies targeting this mechanism. This brief review will provide a personal perspective on HDL research that has benefited from the contributions of many different laboratories (Table 1).