The desmosomal cadherins, comprising the desmogleins and desmocollins, are calcium-dependent transmembrane adhesion molecules that are essential for the cell adhesive role of desmosomes. Until recently, three mouse and three human desmoglein isoforms had been characterized that are expressed in a tissue- and differentiation-specific manner. Very recently, however, we revealed genetic evidence for the presence of a fourth human gene, DSG4. Here we present genetic evidence for the mouse DSG4 homolog as well as two additional novel mouse desmoglein genes situated within the mouse cluster. We have named these two new genes DSG5 and DSG6, both of which demonstrate close homology with mouse DSG1. Mouse DSG4 comprises 16 exons spanning 36 kb of 18q, whereas DSG5 and DSG6 comprise 15 exons spanning approximately 33 kb and 37 kb, respectively, of 18q. The mouse desmoglein 4 transcript contains an open reading frame of 3123 bp, encoding a precursor of 1041 amino acids. The desmoglein 5 transcript contains an open reading frame of 3180 bp encoding a precursor of 1060 amino acid residues, and the desmoglein 6 transcript contains an open reading frame of 2733 bp encoding a precursor of 911 amino acid residues. Using mouse tissue cDNA we have demonstrated that mouse desmogleins 4, 5, and 6 are all expressed in the epidermis but are expressed during different times of mouse development.