We conducted an ecoregional assessment of sagebrush (Artemisia spp.) ecosystems in the Wyoming Basins and surrounding regions (WBEA) to determine broad-scale species-environmental relationships. Our goal was to assess the potential influence from threats to the sagebrush ecosystem on associated wildlife through the use of spatially explicit occurrence and abundance models. These models were developed using information from field surveys conducted along gradients of vegetation productivity and human disturbance integrated with spatial datasets delineating land cover, topography, and human land use in the WBEA area. Our evaluation included all sagebrush-associated wildlife species across multiple taxa whose habitat requirements and distributions were appropriate for modeling and interpretation at the broad scales of this assessment. Dominant land uses were included in delineating the human footprint. Although overall levels of the cumulative human footprint were generally low across the WBEA area, oil and gas activities have decreased the amount of shrubland habitats and increased fragmentation within development regions over the last century. At the scale of this assessment, the influence of humans was primarily expressed as an indirect function through actions that altered or reduced available habitat. We identified 65 plant species of conservation concern; 28 of 40 vertebrate species associated with sagebrush were species of concern in at least one state. We modeled environmental relationships for 15 wildlife species from data collected from surveys conducted in 2005 and 2006 designed to sample multiple species and taxa along land cover and land use gradients across the WBEA area. Occurrence of 3 species was negatively influenced by human features; anthropogenic features were a positive influence for 3 species, 8 had a mixed response, and 1 had no measurable relationship. Sagebrush land cover, considered in all wildlife models, was important to most species but differed among species in the proportion of sagebrush required and at what spatial extent. For most species examined, the spatial extent at which sagebrush cover influenced the probability of occupancy was much larger than an individual’s home range size. Exotic plants were strongly associated with human features, particularly roads, which may function as linear vectors to facilitate spread of exotic plants across the WBEA area. We used coarse-grained spatial and thematic data because of the large spatial extent (350,000 km²) of the WBEA area and the need for a consistent land cover map for the region. Distributions of species occurrence or abundance mapped in this assessment need to be corroborated with information on population demographics. In addition, our results should be interpreted relative to assumptions inherent in broad-scale ecoregional assessments. Our assessment provides managers with extensive and detailed maps of occurrence and abundance, allowing for status assessments of native species, diversity and richness, natural communities, and ecological systems present within the Wyoming Basins.