Abstract Apolipoprotein (apo) A-I accounts for 70% of the total protein in high-density lipoprotein (HDL) and plays a key role in HDL biogenesis and function. Analyses of the apoA-I amino acid sequence have revealed that most of its 243 amino acid residues are grouped into amphipathic α-helices of 11 or 22 amino acids in length. Since the hydrophobic C-terminal domain (residues 190–243) of the human apoA-I molecule is critical for lipid binding, deletion of this segment reduces the ability of the protein to solubilize lipid. Sixteen different types of homozygous, compound heterozygous, and heterozygous apoA-I deficiencies, including large deficiency, inversion, frameshift, and nonsense mutations, have been reported. Most of the missense mutations causing low HDL cholesterolemia are associated with alterations to amino acids 143–187, forming α-helices 6–7 of apoA-I. Mutations in this region are accompanied by activation failure of lecithin:cholesterol acyltransferase (LCAT). Other point mutations leading to low HDL cholesterolemia include ApoA-I(S36A), (K107del), (R173C)Milano, (L178P), and (E235del)Nichinan. Twenty-one mutations that cause amyloidosis have been reported. The hereditary amyloidogenic mutations are clustered within amino acids 26−107 and 154−178 of apoA-I. ApoA-I (R151C)Paris and ApoA-I (R173C)Milano are rare cysteine variants that can form dimers. ApoA-IMilano, in particular, has been proven to exert anti-atherogenic effects in animal studies and small clinical trials. Although there are difficulties associated with its formulation, clinical applications are expected.