Summary Desmoglein 1 is a member of the desmosomal cadherin family that comprise the desmogleins and desmocollins. The desmoglein 1 gene (DSG1) is centromeric to the desmoglein gene cluster and spans ≈ 45 kb of 18q12, comprising 15 exons. The transcript encodes a precursor protein of 1049 amino acids that is cleaved to yield a mature protein of 1000 residues. This mature protein is expressed in certain specialized epithelia, and in the epidermis is expressed within the superficial layers. Within the desmosome the extracellular domain of the protein is essential for calcium dependent heterophilic binding to the desmocollins, whereas the intracellular domain is essential for binding to the desmosomal plaque protein, plakoglobin. Desmoglein 1 has been implicated in several human diseases. Mutations within the extracellular domain lead to autosomal dominant striate palmoplantar keratoderma, whereas autoantibodies and strains of Staphylococcus aureus target the extracellular domain in the acquired bullous disorders pemphigus foliaceus and staphylococcal scalded skin syndrome, respectively. Therefore, intact and functionally active desmoglein 1 is essential to epidermal integrity. Here, we review the expression, protein structure, genetics, and molecular interactions of desmoglein 1 and outline the role it plays within the desmosome and how it becomes defective in human disease.