Aphids are major insect pests of plants that feed directly from the phloem. We used the model legume Medicago truncatula Gaert. (barrel medic) to elucidate host resistance to aphids and identified a single dominant gene which confers resistance to Acyrthosiphon kondoi Shinji (bluegreen aphid). To understand how this gene conditions resistance to bluegreen aphid, transcription profiling of 23 defense-related genes representing various signaling pathways was undertaken using a pair of near-isogenic lines that are susceptible or resistant to bluegreen aphid. All salicylic acid- and ethylene-responsive genes tested were induced by bluegreen aphid in resistant and susceptible plants, although there were some differences in the magnitude and kinetics of the induction. In contrast, 10 of 13 genes associated with the octadecanoid pathway were induced exclusively in the resistant plants following bluegreen aphid infestation. These results are in contrast to plant-pathogen interactions where similar sets of defense genes typically are induced in compatible interactions, but to a lesser degree and later than in incompatible interactions. Treatment of susceptible plants with methyl jasmonate reduced bluegreen aphid infestation but not to the same levels as the resistant line. Together, these results strongly suggest that the octadecanoid pathway is important for this naturally derived aphid resistance trait.