Ecological systems are complex, nonlinear, and dynamic. Studying their responses to pervasive anthropogenic change is both imperative and challenging. Infectious diseases embody this challenge. As the landscape of infectious diseases rapidly shifts—concurrent with climate change, land use change, global movement and trade, and changes in species diversity—how do we isolate the causal mechanisms and predict (and prevent) future outbreaks sparked by global change? Here, we investigate the role of changes in climate and land use in driving the emergence, shift, and expansion of infectious disease transmission. We apply both mechanistic models and causal inference tools to dissect and quantify the impact of global change on disease. First, we show that while climate warming generally drives shifts in vector-borne diseases, rather than widespread expansion, dengue is an exception. Both directional climate warming and extreme climate events can cause major increases in dengue cases and expansion into new regions. For wild plant pathogens, we show that historical climate predicts sensitivity to warm temperatures, but that agricultural pathogens are uniquely sensitive to warming. Next, we show how road paving, deforestation, illegal gold mining, and agricultural intensification can affect malaria, dengue, schistosomiasis, and leishmaniasis, each corresponding to the unique ecology of their hosts and vectors. Synthesizing, we find that the impacts of global change on vector-borne disease dynamics are large, pervasive, locally specific, and yet predictable by combining analytical tools and emerging datasets to understand changing systems.