The number of combinations of anthropogenic stressors affecting global change is increasing; however, few studies have empirically tested for their interactive effects on ecosystems. Most importantly, interactions among ecological stressors generate nonadditive effects that cannot be easily predicted based on single-stressor studies. Here, we corroborate findings from an in situ mesocosm experiment with evidence from a whole-ecosystem manipulation to demonstrate for the first time that interactions between climate and acidification determine their cumulative impact on the food-web structure of coldwater lakes. Interactions among warming, drought, and acidification, rather than the sum of their individual effects, best explained significant changes in planktonic consumer and producer biomass over a 23-year period. Further, these stressors interactively exerted significant synergistic and antagonistic effects on consumers and producers, respectively. The observed prevalence of long- and short-term ecological surprises involving the cumulative impacts of multiple anthropogenic stressors highlights the high degree of uncertainty surrounding current forecasts of the consequences of global change.