High levels of species diversity hamper current understanding of how tropical forests may respond to environmental change. In the tropics, water availability is a leading driver of the diversity and distribution of tree species, suggesting that many tropical taxa may be physiologically incapable of tolerating dry conditions, and that their distributions along moisture gradients can be used to predict their drought tolerance. While this hypothesis has been explored at local and regional scales, large continental-scale tests are lacking. We investigate whether the relationship between drought-induced mortality and distributions holds continentally by relating experimental and observational data of drought-induced mortality across the Neotropics to the large-scale bioclimatic distributions of 115 tree genera. Across the different experiments, genera affiliated to wetter climatic regimes show higher drought-induced mortality than dry-affiliated ones, even after controlling for phylogenetic relationships. This pattern is stronger for adult trees than for saplings or seedlings, suggesting that the environmental filters exerted by drought impact adult tree survival most strongly. Overall, our analysis of experimental, observational, and bioclimatic data across neotropical forests suggests that increasing moisture-stress is indeed likely to drive significant changes in floristic composition.