AbstractThe human plasma high density lipoproteins (HDL) are a heterogeneous ensemble of five proteins associated with both neutral and polar lipids. The sequences of all five proteins are known. ApoA‐I and apoA‐II are the major protein components; apoC‐I, apoC‐II and apoC‐III are the minor protein components. All these apoproteins spontaneously recombine with phospholipids to give stable lipid‐protein complexes and freely exchange between the two major HDL subclasses, HDL2 and HDL3. In addition, ApoC‐I, apoC‐II, and apoC‐III exchange between HDL and very low density lipoproteins. Furthermore, certain HDL apoproteins are activators for plasma enzymes that are important in lipid metabolism. ApoA‐I and apoC‐I activate lecithin/cholesterol acyltransferase; apoC‐II is an activator of lipoprotein lipase. The regions of apoC‐I and apoC‐II that are involved in the activation of these enzymes have been localized with synthetic peptides. Studies of synthetic and native fragments of apoA‐II, apoC‐I, apoC‐II, and apoC‐III as well as model lipid‐binding peptides have identified specific regions with structural features common to lipid‐binding proteins. These special properties, which include helical potential, sequences with a critical amphipathic length, and high hydrophobicity of the nonpolar side of the amphipathic helix, are the determinants of HDL structure and metabolism.