Compelling evidence documents that chemical pollution, including exposure to persistent organic pollutants (POPs), plays an important role in marine wildlife health. The link between the burden of disease and the burden of persistent organic pollutants in marine wildlife species is not well established. To address this challenge, tools are needed for mechanistic and quantitative understanding of chemical exposure and its toxicological implications. This chapter reviews the current approaches and points out the need for a more integrated methodological framework for linking chemical exposure and mixture effects. The existing extraction methods and targeted nature of chemical analysis have limited our capability of assessing the entire mixture of POPs as an entity, thus warranting continuous development of quantitative, unbiased sampling techniques. On the other hand, we need further mechanistic, quantitative understanding of biological pathways linking chemical exposure to adverse health outcomes to design a focused, meaningful test battery of bioassays for comprehensive toxicological profiling of POP mixtures. These advances will be an important step toward understanding the contribution of POPs to the overall impact of environmental threats on marine wildlife population health, which will in turn inform management options for wildlife conservation.