Climate change, globalization, urbanization, social isolation, and increased interconnectedness between physical, human, and technological systems pose major challenges to disaster risk reduction (DRR). Subsequently, economic losses caused by natural hazards are increasing in many regions of the world, despite scientific progress, persistent policy action, and international cooperation. We argue that these dramatic figures call for novel scientific approaches and new types of data collection to integrate the two main approaches that still dominate the science underpinning DRR: the hazard paradigm and the vulnerability paradigm. Building from these two approaches, here we propose a research framework that specifies the scope of enquiry, concepts, and general relations among phenomena. We then discuss the essential steps to advance systematic empirical research and evidence-based DRR policy action. Plain Language Summary The recent deadly earthquake in Iran-Iraq has been yet another reminder of the topicality of natural hazards, and it has come just after an unprecedented series of catastrophic events, including the extensive flooding in South Asia and the string of devastating hurricanes in the Americas. He we identify three main puzzles in the nexus of natural hazards and vulnerabilities, and demonstrate how novel approaches are needed to solve them with reference to a flood risk example. Specifically, we show how a new research framework can guide systematic data collections to advance the fundamental understanding of socionatural interactions, which is an essential step to improve the development of policies for disaster risk reduction.