Desmoglein-3 (DSG3) is a calcium binding membrane protein that is localized desmosome cellular junctions and interacts with plaque proteins and intermediate filaments at cell-cell adhesion points. Desmosomes are cell-cell junctions between epithelial, myocardial and other cells types. In human keratinocytes, Desmoglein-3 (DSG3) is raft associated and disruption of rafts prevents desmosome assembly. DSG3 is one of four sister proteins in the desmoglein family. DSG3 is also the autoantigen for pemphigus vulgaris (PV) a lethal skin disease that is a result of autoantibodies against DSG3. DSG3 is over-expressed in lung squamous cell carcinomas (SQCC) but had very limited expression in both adenocarcinomas and non-neoplastic lungs. Using immunohistochemistry, the sensitivity and specificity of DSG3 for lung cancers were 98% and 99%, respectively, which is similar to that of p40. Therefore, DSG3 can be a useful ancillary marker to separate SQCC from other subtypes of lung cancer.