ABSTRACT Phenotypic plasticity enables an immediate response to changing conditions, but for most species, evolutionary change through adaptation will be more important for long-term survival. Warming climate and increasing desertification urges the identification of genes involved in heat-and dehydration-tolerance to better inform and target biodiversity conservation efforts. Comparisons among extant desert adapted species can highlight parallel or convergent patterns of genome evolution through the identification of shared signatures of selection. We generate chromosome-level genome assembly for the canyon mouse ( Peromyscus crinitus ) and test for signature of parallel evolution by comparing signatures of selective sweeps across population-level genomic resequencing data from another desert specialist deer mouse ( P. eremicus ) and a widely-distributed habitat generalist ( P. maniculatus ), that may locally adapted to arid conditions. We identify few shared candidate loci involved in desert adaptation and do not find support for a shared pattern of parallel evolution. Instead, we hypothesize divergent molecular mechanisms of desert adaptation among deer mice, potentially tied to species-specific historical demography, which may limit or enhance adaptation. We identify a number of candidate loci experiencing selective sweeps in the P. crinitus genome that are implicated in osmoregulation ( Trypsin, Prostasin ) and metabolic regulation ( Kallikrein, eIF2-alpha kinase GCN2, APPL1/2 ), which may be important to accommodating hot and dry environmental conditions.