Cytological analysis of wheat infested by the Hessian fly,Mayetiola destructor(Say), indicated that on susceptible plants, virulent larvae (biotype L, virulent to resistance genes H3,5,6,7/8) caused a generalized increase in cuticular-membrane permeability of cells in the lower leaf sheath. On resistant plants, feeding by avirulent larvae (biotype GP, no genes for virulence) resulted in localized responses. This suggests that plant responses limited the ability of avirulent larvae to elicit generalized changes in cell permeability. Analyses of plant protein patterns by polyacrylamide gel electrophoresis and immunoblots indicated that separate changes in protein metabolism occurred in susceptible versus resistant wheat in association with Hessian fly infestation. In susceptible wheat, ribulose-l,5-bisphosphate carboxylase (Rubisco) increased in the lower leaf sheath in association with infestation. In resistant wheat (cv. Caldwell, H6gene for resistance), proteins of low molecular weight appeared in the lower leaf sheath in association with infestation by avirulent larvae. Protein changes associated with infestation were not elicited by physical wounding of plants. Protein changes detected in resistant wheat infested by avirulent larvae (biotype GP) did not appear when the plants were infested with virulent larvae (biotype L). Results support the hypothesis that hypersensitivity is the phenotypic basis of resistance in the Hessian fly-wheat interaction and involves “recognition” of an avirulence gene product or process.