Desmosomes are adhesive intercellular junctions that link adjacent cells and provide anchoring points for the keratin filament cytoskeleton. The mechanical integrity of desmosomes depends on a complex network of transmembranous and cytoplasmic proteins and glycoproteins each encoded by distinct genes. Recently, naturally occurring human mutations in one of these desmosomal structural components, plakophilin 1, have been described. The clinical features of the affected individuals, who have total ablation of plakophilin 1, comprise a combination of skin fragility and ectodermal dysplasia with loss of hair, reduced sweating and nail dystrophy. Desmosomes in the skin are small and poorly formed and there is widening of intercellular spaces between keratinocytes as well as detachment of the keratin filament network from the cell membrane. These clinicopathological observations demonstrate the relevance of plakophilin 1 to keratinocyte adhesion and epidermal morphogenesis. This new form of genodermatosis represents the first example of human desmosome gene mutations and its clinical and ultrastructural characteristics are highlighted in this article.