The fifth- and ninety-fifth-percentile concentrations of low-density lipoprotein (LDL) cholesterol in most Western populations are approximately 90 and 200 mg/dl, respectively. Persons with LDL cholesterol levels equal to or less than the fifth percentile are defined as having hypobetalipoproteinemia. Epidemiologic studies show that such individuals have lower-than-average risk for atherosclerotic cardiovascular disease but higher risk for a variety of cancers, pulmonary, and gastrointestinal diseases than persons with higher levels of cholesterol. The reasons for this are not known, nor are the causes of most cases of hypobetalipoproteinemia. However, in some well-studied kindreds the hypobetalipoproteinemia phenotype is inherited as an autosomal dominant trait. Heterozygotes in such kindreds are usually healthy and have no difficulty absorbing dietary fat. In most kindreds, the molecular variants responsible for the hypobetalipoproteinemia are unknown, but a subset of kindreds have strong genetic linkages between the low-cholesterol phenotype and truncation-producing mutations of the apolipoprotein (apo) B-100 gene. The truncations of apoB are named according to a centile nomenclature. The full-length 4536-amino acid protein is called apoB-100, and the 25 truncations identified to date have been named apoB-2 to apoB-89. The mutations introduce premature termination codons resulting from frameshift-producing base additions or deletions. The mutations produce slowed rates of secretion of the truncated apoBs relative to the apoB-100s present in the heterozygotes. In addition, the apoB-100 molecules of the heterozygotes are also secreted at rates slower than those observed in closely matched normolipidemic controls. These physiologic results account for the hypobetalipoproteinemia of these subjects. The response of the plasma lipoproteins of heterozygotes to the manipulation of various dietary components remains to be determined. Additional low-cholesterol syndromes are autosomal recessive forms of hypobetalipoproteinemia, chylomicron retention disease, and abetalipoproteinemia. The molecular causes of the first two are unknown. Abetalipoproteinemia is an autosomal recessive condition resulting from mutations of the microsomal triglyceride transfer protein. All three conditions are characterized by vanishingly small concentrations of LDL, dietary fat malabsorption, and failure to thrive in infancy.