Coastal upwelling ecosystems around the world are defined by wind-generated currents that bring deep, nutrient-rich waters to the surface ocean where they fuel exceptionally productive food webs. These ecosystems are also now understood to share a common vulnerability to ocean acidification and hypoxia (OAH). In the California Current Large Marine Ecosystem (CCLME), reports of marine life die-offs by fishers and resource managers triggered research that led to an understanding of the risks posed by hypoxia. Similarly, unprecedented losses from shellfish hatcheries led to novel insights into the coastal expression of ocean acidification. Partnership for Interdisciplinary Studies of Coastal Oceans (PISCO) scientists and other researchers in the CCLME responded to the rise of OAH with new ocean observations and experiments. This work revealed insights into the expression of OAH as coupled environmental stressors, their temporal and spatial variability, and impacts on species, ecological communities, and fisheries. Sustained investigations also deepened the understanding of connections between climate change and the intensification of hypoxia, and are beginning to inform the ecological and eco-evolutionary processes that can structure responses to the progression of ocean acidification and other pathways of global change. Moreover, because the severity of the die-offs and hatchery failures and the subsequent scientific understanding combined to galvanize public attention, these scientific advances have fostered policy advances. Across the CCLME, policymakers are now translating the evolving scientific understanding of OAH into new management actions.