Population studies have shown that plasma HDL levels correlate inversely with cardiovascular disease risk. In recent years there has been intense interest in developing strategies for exploiting these cardioprotective properties by increasing HDL levels. While this approach has considerable merit, it is important to recognize that HDL are structurally and functionally diverse and consist of numerous, highly dynamic subpopulations of particles that do not all inhibit atherosclerosis to the same extent. For this reason it is essential to assess HDL subpopulation distribution and functionality when considering therapeutic interventions that raise HDL levels. This review documents what is known about the relationship between the metabolism and function of HDL subpopulations and how this affects their cardioprotective properties.