Rat peritoneal mast cells (RPMC) exposed to protoporphyrin (PP) and incandescent light (IL) become refractory to the stimulatory effects of compound 48/80. Once initiated, this refractory state continues to develop even after removal of the light source and is essentially complete within 30 min. While this state of unresponsiveness appears to be relatively permanent in the dark, prolonged incubation in the light (greater than 80 min) induces cell lysis. We have shown that the resistant state is not specific for the mast cell stimulator compound 48/80. Mast cells passively sensitized with IgE and illuminated for 30 min in the presence of 100 ng/ml PP also fail to release histamine upon stimulation by anti-rat IgE, anti-rat F(ab')2, concanavalin-A (Con-A), and the calcium ionophore A23187. The inability to respond to immunological stimuli could not be ascribed to the reversible loss of membrane-bound IgE from its receptor. While the binding of either the inducer to IgE or IgE to its receptor may actually be impaired in refractory cells, the significance of such impairments on the development of the resistant state in these cells is precluded by the inability of A23187 to either increase intracellular 45Ca2+ levels or induce histamine release. The data suggest that the RPMC refractory state develops as a result of covalent inter- and/or intramolecular cross-linking of membrane proteins. Furthermore, this cross-linking may involve sulfhydryl or amino groups essential to either stimulus transduction, or the histamine secretory process itself.