Involucrin is a keratinocyte protein that first appears in the cell cytosol, but ultimately becomes cross-linked to membrane proteins by transglutaminase. The gene for human involucrin has now been cloned and sequenced. The central segment of the coding region contains 39 repeats of a 30 nucleotide sequence whose ten encoded amino acids include three glutamines and two glutamic acids. This segment must have originated by successive duplications. Later duplications of modified sequences within the central segment can also be identified. Flanking the central segment lie shorter coding segments, a part of which must have given rise to the central segment. The flanking segments also show homology to a simpler 30 nucleotide sequence from which they likely originated. The evolution of involucrin as a substrate of transglutaminase and an envelope precursor was evidently made possible by this process of repeated mutation and duplication.