To better characterize the proposed growth modulatory functions of mast cells and their products in the regulation of epidermal homeostasis, we have assessed keratinocyte proliferation by incorporation of [3H]thymidine in murine skin organ cultures after incubation with different concentrations of histamine, serotonin or TNF-alpha. Both histamine and serotonin significantly stimulate the proliferation of keratinocytes as compared to controls (P < 0.001), reaching maxima within a range from micro- to nanomolar concentrations. Even at subnanomolar concentration, TNF-alpha significantly inhibits the incorporation of labelled thymidine by epidermal keratinocytes in murine skin organ culture (P < 0.001). These observations support the concept of mast cell products as modulators of keratinocyte proliferation, and suggest a role for mast cells in the regulation of epidermal tissue turnover under physiological conditions.