Climate change is intensifying the effects of multiple interacting stressors on aquatic ecosystems, particularly in estuaries. In the San Francisco Estuary, signals of climate change are apparent in the long-term monitoring record. Here we synthesize current and potential future climate change effects on three main ecosystems (floodplain, tidal marsh, and open water) in the upper estuary and two representative native fishes that commonly occur in these ecosystems (anadromous Chinook Salmon, Oncorhynchus tshawytscha and estuarine resident Sacramento Splittail, Pogonichthys macrolepidotus). Based on our review, we found that the estuary is experiencing shifting baseline environmental conditions, amplification of extremes, and restructuring of physical habitats and biological communities. We present priority topics for research and monitoring, and a conceptual model of how the estuary currently functions in relation to climate variables. In addition, we discuss four tools for management of climate change effects: regulatory, water infrastructure, habitat development, and biological measures. We conclude that adapting to climate change requires fundamental changes in management.