The San Francisco Estuary Regional Monitoring Program (RMP) for Trace Substances is an innovative partnership among a regulatory agency, more than 70 regulated entities, and an independent scientific organization. The institutional arrangement behind the RMP has made the regulatory system increasingly responsive to emerging management needs, particularly with regard to the development of total maximum daily loads and ecosystem impairment assessment. Through multi-agency partnerships within and outside the RMP institutional structure, major information gaps for several pollutants of concern have been narrowed, resulting in a successful consensus-based regulatory approach to managing copper and nickel mass inputs into the Estuary. Short-term research efforts, based upon monitoring results, helped identify the most cost-effective control and remediation options for various bioaccumulative substances. Additionally, adaptive changes to the monitoring program documented the existence of widespread aquatic toxicity in the Estuary that is apparently due to pesticide runoff from agricultural and urban areas. One of the most important contributions of this collaborative monitoring program is the deliberate and systematic adjustment of management and research questions that serve to influence and add relevance to the overall research agenda related to San Francisco Estuary ecosystem assessment.