Low levels of high density lipoprotein (HDL) cholesterol have been associated with an increased risk of coronary heart disease. In this chapter, we discuss the compositional and functional heterogeneity of HDL particles. We briefly describe different approaches to HDL particle characterization (by size, by apolipoprotein content, by protein content) and concentrate specifically on characterization by two-dimensional gel electrophoresis, immunoblotting, and image analysis. We describe the presence of distinct apolipoprotein A-I containing HDL particles and their major apolipoprotein compositions. These particles include very small, discoidal preβ-1 precursor HDL, very small discoidal α-4 HDL, small semi-spherical α-3 HDL, medium spherical α-2 HDL, and large spherical α-1 HDL. In addition, we review recent findings related to HDL proteomics and to possible new functions of HDL. In addition to reverse cholesterol transport, HDL has a large variety of other functions, as evidenced by the discovery of a large number of complement proteins, proteases, coagulation proteins, and proteins associated with HDL and involved in angiogenesis, cell adhesion, oxidation, and hemoglobin metabolism. These observations suggest an important role for HDL particles in the immune response, proteolysis, coagulation, angiogenesis, and other processes.