Recent climate change should result in expansion of species to northern or high elevation range margins, and contraction at southern and low elevation margins in the northern hemisphere, because of local extirpations or range shifts or both. We combined museum occurrence records from both the continental U.S. and Mexico with a new eco-physiological model of extinction developed for lizard families of the world to predict the distributions of 30 desert-endemic reptile and amphibian species under climate change scenarios. The model predicts that 38 % of local populations will go extinct in the next 50 years, across all 30 species. However, extinctions may be attenuated in forested sites and by the presence of montane environments in contemporary ranges. Of the 30 species, three were at very high risk of extinction as a result of their thermal limits being exceeded, which illustrates the predictive value of ecophysiological modeling approaches for conservation studies. In tandem with global strategies of limiting CO2 emissions, we propose urgent regional management strategies for existing and new reserves that are targeted at three species: Barred Tiger Salamander (Ambystomatidae: Ambystoma mavortium stebbinsi), Desert Short-horned Lizard (Phrynosomatidae: Phrynosoma ornatissimum), and Morafka's Desert Tortoise (Testudinidae: Gopherus morafkai), which face a high risk of extinction by 2070. These strategies focus on assisted migration and preservation within climatic refugia, such as high-elevation and forested habitats. We forecast where new reserves should be established by merging our model of extinction risk with gap analysis. We also highlight that acclimation (i.e., phenotypic plasticity) could ameliorate risk of extinction but is rarely included in ecophysiological models. We use Ambystoma salamanders to show how acclimation can be incorporated into such models of extinction risk.