Background/Question/Methods Predicting how human-induced climate change will affect animal distribution, abundance and diversity requires an understanding of the mechanisms underlying both the direct and indirect effects. Although little studied, among the most important direct effects may be catastrophic mortality associated with extreme heat and drought. Climate models predict an increase in both the frequency and severity of these extreme climate events, and historical records demonstrate the potential for catastrophic mortality. Here we quantify the functional mechanisms underlying avian mortality associated with heat stress and the lack of water. We develop a physiological model that predicts rates of evaporative water loss and survival times as a function of body mass and dehydration tolerance. Results/Conclusions Applying the model to current and projected maximum air temperatures predicts that a projected ~5°C increase in maximum air temperatures will increase rates of evaporative water loss by more than 75% and reduce survival times by more than 40% for very small birds.  For birds weighing < 100g (more than 80% of species in most desert bird communities), rates of evaporative water loss should increase by more than 50% and survival times can be reduced by more than 34%. Current and historical accounts already document catastrophic mortality caused by hyperthermia or through dehydration.  Our projections suggest that increasing global temperatures, combined with increased frequency and intensity of heat waves and drought, will result in more frequent catastrophic mortality, and could depopulate regional bird communities.