Human effects on estuaries are often associated with major decreases in abundance of aquatic species. However, remediation priorities are difficult to identify when declines result from multiple stressors with interacting sublethal effects. The San Francisco Estuary offers a useful case study of the potential role of contaminants in declines of organisms because the waters of its delta chronically violate legal water quality standards; however, direct effects of contaminants on fish species are rarely observed. Lack of direct lethality in the field has prevented consensus that contaminants may be one of the major drivers of coincident but unexplained declines of fishes with differing life histories and habitats (anadromous, brackish, and freshwater). Our review of available evidence indicates that examining the effects of contaminants and other stressors on specific life stages in different seasons and salinity zones of the estuary is critical to identifying how several interacting stressors could contribute to a general syndrome of declines. Moreover, warming water temperatures of the magnitude projected by climate models increase metabolic rates of ectotherms, and can hasten elimination of some contaminants. However, for other pollutants, concurrent increases in respiratory rate or food intake result in higher doses per unit time without changes in the contaminant concentrations in the water. Food limitation and energetic costs of osmoregulating under altered salinities further limit the amount of energy available to fish; this energy must be redirected from growth and reproduction toward pollutant avoidance, enzymatic detoxification, or elimination. Because all of these processes require energy, bioenergetics methods are promising for evaluating effects of sublethal contaminants in the presence of other stressors, and for informing remediation. Predictive models that evaluate the direct and indirect effects of contaminants will be possible when data become available on energetic costs of exposure to contaminants given simultaneous exposure to non-contaminant stressors.