Harmful algal blooms (HABs) are on the rise worldwide. Known drivers for the proliferation and intensification of HAB events include increasing nutrient pollution, climate change, regulation and modification of hydrological flow, and the combined effect of climate drivers and nutrient pollution. The San Francisco Bay–Delta system has largely been immune to severe or acute HAB events, but there is both a potential and realized threat which has been underestimated and under-reported, in part because of the lack of coordinated sampling and data reporting. There is also increasing evidence that HABs must be considered in the context of a freshwater-to-marine continuum, and that the physical and political boundaries separating components of the Bay–Delta system are porous barriers to HABs and their toxins. Much remains to be learned about the ecology and physiology of HAB organisms in this system, but five primary environmental drivers can be identified: temperature, salinity, irradiance, nutrients, and stratification/residence time. All these drivers are responding rapidly to climate change, but nutrients are the primary variable that is largely under human control. Plans for the development of a comprehensive monitoring, prediction, and mitigation strategy across the freshwater-to-marine continuum have been documented; effectively following through on these plans provides a roadmap toward identifying the drivers and threats—and reducing the potential consequences now and in the future. While HABs alone are not a sufficient motivator for potentially costly and extensive mitigation efforts, there is strong evidence that decreasing nutrient loads, maintaining hydrological connectivity while minimizing stagnant regions, and managing the biota to maintain biodiversity of the Bay–Delta system will result in multiple co-benefits, including reduction of the HAB threat potential.