Systemic risks are characterized by high complexity, multiple uncertainties, major ambiguities, and transgressive effects on other systems outside of the system of origin. Due to these characteristics, systemic risks are overextending established risk management and create new, unsolved challenges for policymaking in risk assessment and risk governance. Their negative effects are often pervasive, impacting fields beyond the obvious primary areas of harm. This article addresses these challenges of systemic risks from different disciplinary and sectorial perspectives. It highlights the special contributions of these perspectives and approaches and provides a synthesis for an interdisciplinary understanding of systemic risks and effective governance. The main argument is that understanding systemic risks and providing good governance advice relies on an approach that integrates novel modeling tools from complexity sciences with empirical data from observations, experiments, or simulations and evidence-based insights about social and cultural response patterns revealed by quantitative (e.g., surveys) or qualitative (e.g., participatory appraisals) investigations. Systemic risks cannot be easily characterized by single numerical estimations but can be assessed by using multiple indicators and including several dynamic gradients that can be aggregated into diverse but coherent scenarios. Lastly, governance of systemic risks requires interdisciplinary and cross-sectoral cooperation, a close monitoring system, and the engagement of scientists, regulators, and stakeholders to be effective as well as socially acceptable.