SummaryDrug therapy of epidermolysis bullosa dystrophica (E.B.D.) for the past forty years is reviewed.A reproducible method for the direct extraction of collagenase and collagen peptidase from skin homogenates is described.Markedly elevated collagenase and collagen peptidase activity is demonstrated in skin of dystrophic E.B. patients. Diphenylhydantoin in pharmacological doses is shown to cause significant inhibition of the collagenolytic system both in vitro and in vivo. Diphenylhydantoin was used parenterally in two children with proven E.B.D. and was found to have a beneficial effect on skin fragility.