The recent isolation of cDNA and genomic DNA clones for human vWF by ourselves and others has finally laid to rest the historical notion that factor VIII and vWF might have a precursor-product or other complex relationship. These two hemostatic activities are clearly present on two distinct proteins, each encoded by a separate gene. Whether ther is coordinate regulation of the factor VIII and vWF genes is still unknown. The structure and structure-function relationships of the vWF protein have been elucidated by many investigators, only some of whom can be cited in this short paper. Together, these molecular biology and protein chemistry studies have shown that vWAgII is the amino-terminal propeptide of vWF, explaining the proportional deficiency of these two plasma proteins in von Willebrand disease (type I). In addition, sites of proteolytic processing, glycosylation, and disulfide bond formation have been defined, and some of the binding functions of mature vWF have been identified with specific amino acid sequences. The protein has a highly repeated structure, suggesting a complex evolutionary history. The A domains of vWF appear to be homologous to complement factor B, and perhaps to component C2, although the biological meaning of this similarity is unknown. Genomic DNA clones have been isolated corresponding to approximately one third of the vWF gene on chromosome 12, and a fragment of the cDNA also hybridizes to uncharacterized sequences on chromosome 22. Preliminary studies in von Willebrand disease have revealed two patients with very large deletions in the vWF gene.(ABSTRACT TRUNCATED AT 250 WORDS)