Smallmouth bass Micropterus dolomieu in the Susquehanna River basin have been a species of interest for over a decade due to continued fish health concerns. Collaborative research efforts have identified a wide range of disease problems as well as potential risk factors. Nevertheless, many data gaps must be filled in order to answer essential questions regarding the past, present, and future health of Susquehanna River smallmouth bass populations. One need, which is limited in data, is to understand organic contaminants in the environment and in fish tissues that are related to observed lesions and functional health impairments in the affected fish. This information is key to setting the stage for better management that will ensure healthy aquatic habitats. Historically, studies that attempted to correlate environmental exposures with disease outcomes have utilized targeted analytical methods. Unfortunately, such an approach excludes many contaminants that may contribute directly or indirectly to resident organism health impacts. Many such prior investigations have, therefore, been inconclusive regarding the correlation between disease and exposure. By developing a more inclusive, discovery-based, analytical approach that can achieve a reasonable sample throughput, far more data could be collected to increase the probability of finding meaningful correlations between contaminant exposures and major disease outcomes. This approach will generate considerably larger data sets, so data reduction procedures that are consistent with the goals of this study will also be developed.