While the influence of antecedent conditions on watershed function is widely recognized under typical hydrologic regimes, gaps remain in the context of extreme climate events (ECEs). ECEs are those events that far exceed seasonal norms of intensity, duration, or impact upon the physical environment or ecosystem. In this synthesis, we discuss the role of source availability and hydrologic connectivity on antecedent conditions and propose a conceptual framework to characterize system response to ECEs at the watershed scale. We present four case studies in detail that span a range of types of antecedent conditions and type of ECE to highlight important controls and feedbacks. Because ECEs have the potential to export large amounts of water and materials, their occurrence in sequence can disproportionately amplify the response. In fact, multiple events may not be considered extreme in isolation, but when they occur in close sequence they may lead to extreme responses in terms of both supply and transport capacity. Therefore, to advance our understanding of these complexities, we need continued development of a mechanistic understanding of how antecedent conditions set the stage for ECE response across multiple regions and climates, particularly since monitoring of these rare events is costly and difficult to obtain. Through focused monitoring of critical ecosystems during rare events we will also be able to extend and validate modeling studies. Cross-regional comparisons are also needed to define characteristics of resilient systems. These monitoring, modeling, and synthesis efforts are more critical than ever in light of changing climate regimes, intensification of human modifications of the landscape, and the disproportionate impact of ECEs in highly populated regions.