Technical Abstract: Wheat and its relatives possess large numbers of resistance genes (R-genes) specific for Hessian fly (HF) [Mayetiola destructor (Say)], an insect that manipulates its host by establishing a nutritive feeding tissue. Many R-genes confer complete resistance to the Hessian fly, i.e. 100% of attacking larvae die within days of initial attack. To counteract this type of resistance, Hessian fly has the ability to differentiate and maintain population heterogeneity, i.e. different genotypes (also referred to as biotypes phenotypically) that can overcome resistance conferred by specific R-genes. The objective of this study was to use the wheat-HF system to study the molecular interactions between host plants and insects. Using two different R-genes, H9 and H13, a genome-wide transcriptional analysis was performed to determine gene expression during two types of interactions: incompatible (R-gene + avirulent larvae) and compatible (R-gene + virulent larvae). A large number of transcripts (1,119) showed significant alterations in gene expression during either compatible or incompatible interactions. Analysis of the genes with known functions revealed that the genes encoding proteins involved in direct defense and the genes encoding enzymes involved in the phenylpropanoid, cell wall, and lipid metabolism pathways, were the major targets for differential regulation during compatible and incompatible interactions. Thus a combination of the enhancement of antibiosis 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. To overcome this resistance, virulent larvae appeared to suppress antibiosis defense, while inducing nutrient metabolism, weakening cell wall, and inhibiting plant growth.