The effects of a variety of retinoids on collagenase and gelatinase expression have been examined in skin fibroblast cultures derived from normal volunteers and from patients with the hereditary blistering disorder, recessive dystrophic epidermolysis bullosa. Both 13-cis- and all-trans-retinoic acid were effective inhibitors of collagenase production in both cell types. In the case of collagenase, the inhibition of collagenase activity was paralleled by a reduction in immunoreactive enzyme protein, suggesting that these retinoids act by inhibiting synthesis and/or secretion of the enzyme. Retinoic acid also inhibited production of the second enzyme in the collagen degradative pathway, gelatinase. In this case, the decrease in gelatinase activity was equal to or slightly greater than that achieved in collagenase expression. The observation that certain retinoids modulate the two crucial enzymes in the degradation of collagen in the skin suggests that they might be useful therapeutic agents in recessive dystrophic epidermolysis bullosa, a disease in which the pathogenesis of blistering is in part related to connective tissue destruction.