Germplasm of Brachypodium distachyon was inoculated with Magnaporthe grisea using either rice- (Guy11) or grass-adapted (FAG1.1.1, PA19w-06, PA31v-01) host-limited forms of the fungus, and interactions with varying degrees of susceptibility and resistance were identified. Ecotype ABR5 was resistant to each M. grisea strain whereas ABR1 was susceptible to all but P31vi-01. Mendelian segregation in ABR1 × ABR5 crosses suggested that a single dominant resistance gene conferred resistance to Guy11. Microscopic analyses revealed that the aetiology of Guy11 fungal development and disease progression in ABR1 closely resembled that of rice infections. In ABR5, Guy11 pathogenesis was first suppressed at 48 h post-inoculation, at the secondary hyphal formation stage and was coincident with cytoplasmic granulation. Resistance to strains PA31v-01 and FAG1.1.1 was associated with a localized cell death with little callose deposition. 3,3-Diaminobenzidine staining indicated the elicitation of cell death in B. distachyon was preceded by oxidative stress in the interacting epidermal cells and the underlying mesophyll cells. Northern blot hybridization using probes for barley genes (PR1, PR5 and PAL) indicated that each was more rapidly expressed in ABR5 challenged with Guy11 although the B. distachyon defence genes BD1 and BD8 were more quickly induced in ABR1. Such data show that B. distachyon is an appropriate host for functional genomic investigations into M. grisea pathology and plant responses.