Climate change-driven sea level rise and altered precipitation regimes are predicted to alter patterns of salt intrusion within the San Francisco Estuary. A central question is: Can we use existing knowledge and future projections to predict and manage the anticipated ecological impacts? This was the subject of a 2018 symposium entitled “Ecological and Physiological Impacts of Salinization of Aquatic Systems from Human Activities.” The symposium brought together an inter-disciplinary group of scientists and researchers, resource managers, and policy-makers. Here, we summarize and review the presentations and discussions that arose during the symposium. From a historical perspective, salt intrusion has changed substantially over the past 10,000 years as a result of changing climate patterns, with additional shifts from recent anthropogenic effects. Current salinity patterns in the San Francisco Estuary are driven by a suite of hydrodynamic processes within the given contexts of water management and geography. Based on climate projections for the coming century, significant changes are expected in the processes that determine the spatial and temporal patterns of salinity. Given that native species—including fishes such as the Delta Smelt and Sacramento Splittail—track favorable habitats, exhibit physiological acclimation, and can adaptively evolve, we present a framework for assessing their vulnerability to altered salinity in the San Francisco Estuary. We then present a range of regulatory and structural management tools that are available to control patterns of salinity within the San Francisco Estuary. Finally, we identify major research priorities that can help fill critical gaps in our knowledge about future salinity patterns and the consequences of climate change and sea level rise. These research projects will be most effective with strong linkages and communication between scientists and researchers, resource managers, and policy-makers.