Aquatic biota in the Sacramento River watershed are stressed by diversion of river flows, by historical mining resulting in cadmium, copper, zinc, and mercury, and, more recently, contamination by agricultural and urban chemical runoff. In addition, the proposed redirection of drainage of saline waters--containing selenium--from the western slope of the San Joaquin River into the Delta formed by the confluence of the Sacramento and San Joaquin Rivers could add to the stress on resident organisms. These combined stressors have led to deterioration in surface water quality and the aquatic habitat. The potential interaction of these stressors, coupled with invasions of foreign species and the export of juvenile fish into aqueducts, has driven several species of fish to near extinction in the system. Effects of historical contamination by heavy metals are potentially exacerbated by presence of organophosphate pesticides, at concentrations exceeding National Academy of Sciences recommendations, throughout the lower watershed and the San Francisco Bay. The Asian clam, Potamocorbula amurensis, an introduced non-indigenous species has apparently become a preferred food item of the sturgeon, Accipenser transmontanus, an important sport and aquaculture species. Since this introduction, sturgeon body burdens for selenium have increased dramatically and analytical chemistry of P. amurensis indicates that these organisms are effective bioaccumulators of selenium. This review examines potential ecotoxicity associated with multiple stressors in the watershed. Data from field monitoring, laboratory toxicity assays with ambient water, and ecotoxicologic investigations are reviewed. Potential designs for multiple stressor investigations are discussed. The information presented on this watershed illustrates the challenge to investigators seeking to evaluate multiple stressor effects on riverine and estuarine organisms.