Poised at the interface of rivers, ocean, atmosphere and dense human settlement, estuaries are driven by a large array of natural and anthropogenic forces. Long-term study of San Francisco Bay illustrates responses to five common agents of change where land and sea meet: water consumption and diversion, human modification of sediment inputs, introduction of nonnative species, regulatory responses to pollution, and climate shifts. Responses to these drivers include modifications of: freshwater inflow and salinity, morphometry and turbidity, food supplies to native fish, dissolved oxygen concentrations, and the structure of biological communities. 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 ecosystems. The many time scales of variability 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.