A genome-wide transcriptional analysis of wheat response to Hessian fly infestation using two isogenic wheat lines that carry two different resistance genes, enabled us to identify 1,220 cDNAs that detected consistent and significant alterations in gene expression during either compatible or incompatible interactions. Functional analysis of the genes with known functions revealed that the genes encoding proteins involved in direct antibiotic defense and the genes encoding enzymes involved in the phenylpropanoid, cell wall, and lipid metabolism were the major targets for differential regulation during compatible and incompatible interactions. Our results indicated that a combination of the enhancement of antibiotic defense, the evasion of nutrient metabolism induction, and the fortification and expansion of the cell wall, are likely the collective mechanism for host plant resistance observed during incompatible interactions. In contrast, induced susceptibility including the suppression of antibiotic defense, the induction of nutrient metabolism, the weakening of cell wall, and the inhibition of plant growth appeared to be the necessary conditions for Hessian fly virulence during compatible interactions.