The structures of the major human apolipoprotein genes have been determined. The genes for apoE, apoC-I, apoC-II, apoC-III, apoA-I, apoA-II and apoA-IV have similar structures, consisting of four exons and three introns, which suggests that they evolved from a common ancestral gene. The third and fourth exons of the ancestral gene appear to have evolved from the duplication of a 66-nucleotide repeat unit that encodes a 22-residue alpha-helical peptide element of amphipathic character. The apoA-I, apoC-III and apoA-IV genes are linked closely within a 20-kilobase (kb) span of chromosome 11. The apoE and apoC-I genes, together with an apoC-I' pseudogene, are linked closely within a 25-kb span of chromosome 19. To characterize potential functional relationships among the apolipoprotein genes, initial studies have been done to identify the molecular elements involved in the regulation of the human apoE gene. Fragments of the 5'-flanking portion of this gene were inserted into appropriate plasmid vectors, which contained the bacterial chloramphenicol acetyl transferase gene, and were examined for promoter activity and potential enhancer activity after transfection into cultured mammalian cells. Deletion mapping of the promoter region has identified multiple functional elements, including an enhancer, two G-C boxes (Sp 1 transcription factor binding sites) and an upstream control element. In addition, there is an enhancer located in the first intron. Interactions among these various control elements are likely to determine the ways in which the expression of the apoE gene is regulated.