Lethal acantholytic epidermolysis bullosa (LAEB) is an autosomal recessive disorder caused by mutations in the gene encoding the desmosomal protein, desmoplakin (DSP). It is recognized as a distinct form of suprabasal epidermolysis bullosa simplex, although only a single case has been reported. The phenotype comprises severe fragility of skin and mucous membranes with marked transcutaneous fluid loss. Other features include total alopecia, neonatal teeth, and anonychia. Skin biopsy reveals abnormal desmosomes with suprabasal clefting and acantholysis and disconnection of keratin intermediate filaments from desmosomes. The DSP abnormalities present in the affected individual involved expression of truncated DSP polypeptides that lacked the tail domain of the protein. This part of DSP has a vital role in binding to keratin filaments. The affected neonate died after 10 days because of heart failure with evidence of loss of epithelial integrity in the skin, lung, gastrointestinal tract, and bladder. This article provides a clinicopathologic overview of this unique desmosomal genodermatosis, set in the context of other DSP gene mutations, both dominant and recessive, that can cause a spectrum of skin, hair, and heart abnormalities.