During the past 15 years, significant efforts have been directed to develop the grass species Brachypodium distachyon as a genetically tractable model for monocot plants, especially economically valuable cereals such as wheat, barley and oat. Such efforts have led to an increasing availability of genomic, genetic and bioinformatics tools designed to bypass the experimental challenges faced when addressing important biological questions in complex systems. Moreover, such advances may translate in the use of other valuable species of Brachypodium (e.g., B. hybridum), which are not nearly as well characterized as B. distachyon. Given the 2050 global food demands and needs to increase grain production we seek to develop innovative and sustainable approaches to decrease crop yield losses due to rust fungi. One possible strategy is the use of transgenic plants harboring non-host resistance-related genes from closely related species. B. distachyon and B. hybridum can serve as potential sources to engineer plant resistance against highly destructive rust fungi, such as Puccinia graminis and P. coronata. Advancing our understanding of non-host resistance in monocot species has been a slow process. However, the amenability of Brachypodium as a model system offers a means to accelerate scientific discovery of factors controlling non-host pathogen interactions involving stem and crown rust fungi. In a multi-pronged approach, we are leveraging genetic and genomic tools, as well as generating new resources to provide foundational knowledge in order to support plant genetic engineering programs.