We have cloned the human genes coding for desmosomal glycoproteins DGII and DGIII, found in desmosomal cell junctions, and sequencing shows that they are related to the cadherin family of cell adhesion molecules. Thus a new super family of cadherin-like molecules exists which also includes the other major desmosomal glycoprotein, DGI (Wheeler, G. N., Parker, A. E., Thomas, C. L., Ataliotis, P., Poynter, D., Arnemann, J., Rutman, A. J., Pidsley, S. C., Watt, F. M., Rees, D. A., Buxton, R. S., and Magee, A. I. (1991) Proc. Natl. Acad. Sci. U.S.A., in press). DGIII differs from DGII by the addition of a 46-base pair exon containing an in-frame stop codon resulting in mature protein molecular weights of 84,633 for DGII and 78,447 for DGIII. The unique carboxyl-terminal region of DGII contains a potential serine phosphorylation site explaining why only DGII is phosphorylated on serine. The cadherin cell adhesion recognition sequence (His-Ala-Val) is replaced by Phe-Ala-Thr, suggesting that DGII/III may be adhesive molecules using a different mechanism.