Across the globe, conflicting priorities exist in how land and resources are managed. In the American West, conflicts are common on public lands with historical mandates for multiple uses. We explored the impacts of multiple uses of land in a case study of Agassiz's Desert Tortoises (Gopherus agassizii), a federally threatened species, in the western Sonoran Desert. The tortoise has declined for many reasons, most of which relate to management of land and habitat. Frequently cited causes are livestock grazing, roads, vehicle-oriented recreation, predators, and disease. In spring of 2009, we conducted a survey to evaluate relationships between desert tortoises, vegetation associations, topography, predators, and anthropogenic uses. We sampled a 93-km2 area with 200 independent 1-ha plots. Density (± SE) of adult tortoises was low, 2.0 ± 1.0/km2, and the annualized death rate for adults during the 4 yr preceding the survey was high, 13.1%/yr. We observed tortoise sign, most of which was recent, on 22% of the 200 plots, primarily in the southwestern part of the study area. More tortoise sign occurred on plots with Brittlebush (Encelia spp.) vegetation at higher elevations. Most plots (91.0%) had ≥1 human-related impacts: feral burro scat (Equus asinus; 84.0%), recent vehicle tracks and trails (34.0%), trash (28.0%), burro trails and wallows (26.5%), and old vehicle tracks (24.0%). We used a multimodel approach to model presence of tortoise sign on the basis of 12 predictor variables, and calculated model-averaged predictions for the probability of tortoise presence. Importance values revealed two apparent top drivers: feral burros and vegetation association. This is the first study to identify a negative association between presence of desert tortoises and feral burros.