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Granivorous rodent populations in deserts are primarily regulated through precipitation-driven resource pulses rather than pulses associated with mast-seeding, a pattern more common in mesic habitats. We studied heteromyid responses to mast-seeding in the desert shrub blackbrush (Coleogyne ramosissima), a regionally dominant species in the Mojave-Great Basin Desert transition zone. In a 5-year study at Arches National Park, Utah, USA, we quantified spatiotemporal variation in seed resources in mast and intermast years in blackbrush-dominated and mixed desert vegetation and measured responses of Dipodomys ordii (Ord’s kangaroo rat) and Perognathus flavescens (plains pocket mouse). In blackbrush-dominated vegetation, blackbrush seeds comprised > 79% of seed production in a mast year, but 0% in the first postmast year. Kangaroo rat abundance in blackbrush-dominated vegetation was highest in the mast year, declined sharply at the end of the first postmast summer, and then remained at low levels for 3 years. Pocket mouse abundance was not as strongly associated with blackbrush seed production. In mixed desert vegetation, kangaroo rat abundance was higher and more uniform through time. Kangaroo rats excluded the smaller pocket mice from resource-rich patches including a pipeline disturbance and also moved their home range centers closer to this disturbance in a year of low blackbrush seed production. Home range size for kangaroo rats was unrelated to seed resource density in the mast year, but resource-poor home ranges were larger (P < 0.001) in the first postmast year, when resources were limiting. Blackbrush seeds are higher in protein and fat but lower in carbohydrates than the more highly preferred seeds of Indian ricegrass (Achnatherum hymenoides) and have similar energy value per unit of handling time. Kangaroo rats cached seeds of these two species in similar spatial configurations, implying that they were equally valued as stored food resources. Blackbrush mast is a key resource regulating populations of kangaroo rats in this ecosystem.