The field of landscape genetics relates habitat features and genetic information to infer dispersal and genetic connectivity between populations or individuals distributed across a landscape. Such studies usually focus on a small portion of a species range, and the degree to which these geographically restricted results can be extrapolated to different areas of a species range remains poorly understood. Studies that have focused on spatial replication in landscape genetics processes either evaluate a small number of sites, are informed by a small set of genetic markers, analyze only a small subset of environmental variables, or implement models that do not fully explore parameter space. Here, we used a broadly distributed ectothermic lizard (Sceloporus occidentalis, Western Fence lizard) as a model species to evaluate the full role of topography, climate, vegetation, and roads on dispersal and genetic differentiation. We conducted landscape genetics analyses in five areas within the Sierra Nevada mountain range, using thousands of ddRAD genetic markers distributed across the genome, implemented in the landscape genetics program ResistanceGA. Across study areas, we found a great deal of consistency in the variables impacting genetic connectivity, but also noted site-specific differences in the factors in each study area. High-elevation colder areas were consistently found to be barriers to gene flow, as were areas of high ruggedness and slope. High temperature seasonality and high precipitation during the winter wet season also presented a substantial barrier to gene flow in a majority of study areas. The effect of other landscape variables on genetic differentiation was more idiosyncratic and depended on specific attributes at each site. Vegetation type was found to substantially affect gene flow only in the southernmost Sequoia site, likely due to a higher proportion of desert habitat here, thereby fragmenting habitats that have lower costs to dispersal. The effect of roads also varied between sites and may be related to differences in road usage and amount of traffic in each area. Across study areas, canyons were always substantially implicated as facilitators to dispersal and key features linking populations and maintaining genetic connectivity across landscapes. We emphasize that spatial data layers are complex and multidimensional, and a careful consideration of associations between variables is vital to form sound conclusions about the critical factors affecting dispersal and genetic connectivity across space.