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Recent elevated temperatures and prolonged droughts in many already water-limited regions throughout the world, including the southwestern United States, are likely to intensify according to future climate-model projections. This warming and drying can negatively affect perennial vegetation and lead to the degradation of ecosystem properties. To better understand these detrimental effects, we formulate a conceptual model of dryland ecosystem vulnerability to climate change that integrates hypotheses on how plant species will respond to increases in temperature and drought, including how plant responses to climate are modified by landscape, soil and plant attributes that are integral to water availability and use. We test the model through a synthesis of fifty years of repeat measurements of perennial plant species cover in large permanent plots across the Mojave Desert, one of the most water-limited ecosystems in North America. Plant species ranged in their sensitivity to precipitation in different seasons, capacity to increase in cover with high precipitation and resistance to decrease in cover with low precipitation. Our model successfully explains how plant responses to climate are modified by biophysical attributes in the Mojave Desert. For example, deep-rooted plants were not as vulnerable to drought on soils that allowed for deep-water percolation, whereas shallow-rooted plants were better buffered from drought on soils that promoted water retention near the surface. Synthesis. Our results emphasize the importance of understanding climate–vegetation relationships in the context of biophysical attributes that influence water availability and provide an important forecast of climate-change effects, including plant mortality and land degradation in dryland regions throughout the world.