Human activities create threats that have consequences for freshwater ecosystems and, in most watersheds, observed ecological responses are the result of complex interactions among multiple threats and their associated ecological alterations. Here we discuss the value of considering multiple threats in research and management, offer suggestions for filling knowledge gaps, and provide guidance for addressing the urgent management challenges posed by multiple threats in freshwater ecosystems. There is a growing literature assessing responses to multiple alterations, and we build off this background to identify three areas that require greater attention: linking observed alterations to threats, understanding when and where threats overlap, and choosing metrics that best quantify the effects of multiple threats. Advancing science in these areas will help us understand existing ecosystem conditions and predict future risk from multiple threats. Because addressing the complex issues and novel ecosystems that arise from the interaction of multiple threats in freshwater ecosystems represents a significant management challenge, and the risks of management failure include loss of biodiversity, ecological goods, and ecosystem services, we also identify actions that could improve decision-making and management outcomes. These actions include drawing insights from management of individual threats, using threat attributes (e.g., causes and spatio-temporal dynamics) to identify suitable management approaches, testing management strategies that are likely to be successful despite uncertainties about the nature of interactions among threats, avoiding unintended consequences, and maximizing conservation benefits. We also acknowledge the broadly applicable challenges of decision-making within a socio-political and economic framework, and suggest that multidisciplinary teams will be needed to innovate solutions to meet the current and future challenge of interacting threats in freshwater ecosystems.