Poised at the interface of rivers, ocean, atmosphere and dense human settlement, estuaries are driven by a large array of natural and anthropogenic forces. San Francisco Bay exemplifies the fast-paced change occurring in many of the world's estuaries, bays and inland seas in response to these diverse forces. We use observations from this particularly well-studied estuary to illustrate responses to six drivers that are common agents of change where land and sea meet: water consumption and diversion; human modification of sediment supply; introduction of non-native species; sewage input; environmental policy; and climate shifts. In San Francisco Bay, responses to these drivers include, respectively, shifts in the timing and extent of freshwater inflow and salinity intrusion; decreasing turbidity; restructuring of plankton communities; nutrient enrichment; elimination of hypoxia and reduced metal contamination of biota; and food web changes that decrease resistance of the estuary to nutrient pollution. Detection of these changes and discovery of their causes through environmental monitoring have been essential for establishing and measuring outcomes of environmental policies that aim to maintain high water quality and sustain services provided by estuarine-coastal ecosystems. The wide range of variability time scales and the multiplicity of interacting drivers place heavy demands on estuarine monitoring programs. But the San Francisco Bay case study illustrates why the imperative for monitoring has never been greater.