Abstract Background Efforts in global heath need to deal not only with current challenges, but also to anticipate new scenarios, which sometimes unfold at lightning speed. Predictive modeling is frequently used to assist planning, but outcomes depend heavily on a subset of critical assumptions, which are mostly hampered by our limited knowledge about the many factors, mechanisms and relationships that determine the dynamics of disease systems, by a lack of data to parameterize and validate models, and by uncertainties about future scenarios. Discussion We propose a shift from a focus on the prediction of individual disease patterns to the identification and mitigation of broader fragilities in public health systems. Modeling capabilities should be used to perform “stress tests” on how interrelated fragilities respond when faced with a range of possible or plausible threats of different nature and intensity. This system should be able to reveal crosscutting solutions with the potential to address not only one threat, but multiple areas of vulnerability to future health risks. Summary Actionable knowledge not based on a narrow subset of threats and conditions can better guide policy, build societal resilience and ensure effective prevention in an uncertain world.