Accurate risk assessment of secondary poisoning by persistent organic pollutants (POPs) in top predators is possible but requires multidisciplinary input from wildlife ecology, ecotoxicology, and analytical chemistry. Because of the transfer of POPs up the food chain, traditional approaches to exposure assessment based on POPs in abiotic compartments or organisms low in the food chain can make the assessment of risk to top predators complicated. For more direct, accurate, and site-specific methods of assessing the risks of secondary poisoning of top predator by POPs, we classify 2 main approaches: diet based and tissue based. Exposure assessment via the diet-based approach requires samples of the predator's diet and measured concentrations in the prey items, realistic estimates of dietary composition, and ingestion rates. The even more direct, tissue-based approach uses measured POP concentrations in tissues of top predators to determine internal exposure coupled with tissue-based effect concentrations (or biological responses measured via biomarkers) to determine risk. The advantage of these methods is that uncertain estimates of POPs transfer to top predators from lower trophic levels are avoided. In practice, the availability of dose–response data and internal exposure–response relationships for POPs in top predators is limited, so these may have to be extrapolated from surrogate species. In this paper we illustrate and evaluate the potential of diet-based and tissue-based risk assessment approaches with case studies and demonstrate that appropriate methodologies significantly reduce the uncertainty in risk assessments of POPs.