The molecular nature of many plant disease resistance (R) genes is known; the largest class encodes nucleotide-binding site-leucine-rich repeat (NBS-LRR) proteins that are structurally related to proteins involved in innate immunity in animals. Few genes conferring disease susceptibility, on the other hand, have been identified. Recent identification of susceptibility to the fungusCochliobolus victoriaeinArabidopsis thalianahas enabled our cloning ofLOV1, a disease susceptibility gene that, paradoxically, is a member of the NBS-LRR resistance gene family. We foundLOV1mediates responses associated with defense, but mutations in known defense response pathways do not prevent susceptibility toC. victoriae. These findings demonstrate that NBS-LRR genes can condition disease susceptibility and resistance and may have implications forRgene deployment.