Despite detailed microscopic descriptions and clinical observation, little is known regarding the pathogenesis of the perforating disorders of skin, which have traditionally been subdivided into numerous microscopic entities associated with various clinical settings. An increasing body of evidence now suggests that the perforating disorders of skin are akin, and may constitute an expanded single pathologic entity. Each of the classic perforating disorders of skin, including elastosis perforans serpiginosa, perforating folliculitis, reactive perforating collagenosis, Kyrle's disease, and perforating disorder of uremia, have been shown to extrude collagen, elastin, and related extracellular matrix components through the epidermis. Considering a shared pathogenic mechanism among these entities, we explored the possible role of the extracellular matrix, in particular fibronectin, in perforating disorders of skin. Using immunohistochemical and serum determinations of extracellular matrix constituents, including fibronectin, collagen type IV, laminin, and tenascin, we showed consistent serum elevation and/or deposition of fibronectin, in each case, without a commensurate increase in laminin, collagen type IV, and tenascin. We propose that elevated serum and tissue concentrations of fibronectin may be responsible for inciting, in a physiologically aberrant manner, increased epithelial migration and proliferation culminating in perforation.