606Throughout their evolutionary history, plants have developed an intricate immune system, including a basal defense response that provides resistance toward a broad range of pathogens, as well as a species or isolate specific recognition response. Biotrophic pathogens, needing living plant tissue to subsist, are successfully sequestered via the initiation of a localized cell death response following the recognition of pathogen avirulence proteins by a dominant resistance gene in the host. This mechanism is classically known as a “gene-for-gene” interaction and has been observed in many biotrophic pathosystems. Intriguingly, necrotrophic pathogens, requiring dead plant tissue for survival, have evolved means to intentionally activate host cell death responses. Inappropriate elicitation of host defense responses by targeted action of pathogen produced necrotrophic effectors on a host dominant susceptibility factor results in programmed cell death, providing a source of nutrients for the necrotroph resulting in a compatible reaction. At the molecular level, this interaction essentially mirrors a “gene-for-gene” model, but the outcome shifts from resistance to susceptibility due to the lifestyle of the phytopathogen. Additionally, as “gene-for-gene” interactions are generally qualitative in nature, these “inverse gene-for-gene” interactions in necrotrophic pathosystems often have an additive or quantitative effect. Characterization of host susceptibility factors show the presence of homologous domains to those of identified resistance genes, further implicating them in typical host defense responses. Necrotrophic effectors, generally observed to be small, secreted proteins with a high cysteine content, evolved to manipulate pieces of the plant immune system for benefit of the pathogen. Four economically important necrotrophic plant pathogens of wheat and barley (Pyrenophora tritici-repentis, Parastagonospora nodorum, Pyrenophora teres, and Cochliobolus sativus) have been observed to cause disease in an “inverse gene-for-gene” manner. Discussed in this chapter, thorough investigation of these interactions at both the genetic and molecular level has shed light on these intricate pathosystems, illustrating the complex evolutionary relationships occurring between plants and necrotrophic pathogens. As resistance to necrotrophic pathogens can be facilitated through the lack of susceptibility genes rather than the presence of resistance genes, the current research of “inverse gene-for-gene” interactions will allow wheat and barley breeders to improve their elite breeding germplasm by selecting against host susceptibility factors.