Four groups of inhibitor-like genes that encode proteins with diverse structures were identified from wheat. The majority of these genes were upregulated by avirulent Hessian fly, Mayetiola destructor (Diptera: Cecidomyiidae), larvae during incompatible interactions, and were downregulated by virulent larvae during compatible interactions. The upregulation during incompatible interactions and downregulation during compatible interactions resulted in four- to 30-fold differences between the expression levels in resistant plants and those in susceptible plants. The increased expression of inhibitor-like genes during incompatible interactions suggested that these genes are part of defense mechanisms in wheat against Hessian fly attacks, whereas the downregulation during compatible interactions suggested that virulent larvae can suppress plant defenses. Both the upregulation of the inhibitor-like genes during incompatible interactions by avirulent larvae and the downregulation during compatible interactions by virulent larvae were through mechanisms that were independent of the wound response pathway.