Physical interactions between proteins play a critical role in the cascade of events associated with the activation of plant defense responses to pathogens. A high-quality large-scale interaction maps for the rice stress response have been developed. We used the rice stress response interactome as a template to start dissecting the protein-protein interaction network controlling disease resistance in wheat. Despite the importance of wheat as a major staple crop and the impact of biotic diseases on its production worldwide, the genetic mechanisms and gene interactions involved in the resistance response in wheat are still poorly understood. As entry points we selected the wheat orthologous copies of four key proteins that control the rice biotic stress response: NH1, XA21, and RAR1, and XB12 (XA21 interacting protein 12). Using available EST collections, BAC libraries, next generation sequencing, and phylogenetic analyses we identified and cloned the wheat orthologous copies of these four rice proteins and their known direct interactors. Gene family expansions that occurred after the rice-wheat divergence were frequently observed probably reflecting different selective pressures exerted by different pathogen types on the two plant species. Pair-wise yeast-2-hybrid (Y2H) tests confirmed that most of the rice interactions also occur in wheat. By screening a Y2H cDNA library constructed from rust leaves infected with Puccinia striiformis f.sp. tritici (the causal agent of wheat stripe rust) we identified additional interactors for the wheat NH1 and XA21 proteins.