Perennial grain production will likely present unique challenges for managing diseases that affect the productivity and longevity of crops being considered. Typical cultural practices effective at reducing soil- and residue-borne pathogens, such as annual crop rotations, delayed fall planting, and tillage, are not feasible in perennial systems. Consequently, soil- and residue-borne pathogens, and pathogens such as root colonizers and viruses that survive in live tissue, may increase in importance in a perennial grain crop. Resistance genes will undeniably be important defenses against disease. However, it is seldom, if ever, possible to incorporate within a single cultivar resistance to all existing and future important diseases. Furthermore, genes vulnerable to ‘boom and bust’ cycles are generally short-lived when deployed in monocultures. For these reasons, the use of mixtures of crop cultivars or species that vary in resistance functions will likely be an important strategy for managing diseases and pests of perennial grains. Burning of plant residue, a natural phenomenon in native perennial grass systems, may also be an effective disease management strategy. The successful implementation of these management tools may reduce or eliminate the risk that perennial grain crops will become pathogen refugia that affect neighboring annual plantings and the productivity of perennial plants.