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Occurrences of fish kills are increasing in aquatic ecosystems worldwide, and have been attributed to natural phenomena, as well as human modification and pollution of terrestrial and aquatic environments. Despite contemporary research activities, the science of fish kill investigations is still rudimentary and has advanced little since the 1960s. Here, we highlight the complexity of fish kills and provide a critical commentary on the key challenges that must be overcome in order to advance the science of fish kill investigation. Such challenges include recognizing the potential for carry-over effects, biotic factors, and multiple stressors when conducting fish kill investigations. We recommend an interdisciplinary approach that includes recent innovations in field physiology, functional genomics, and greater reliance on fish health professionals. We also recommend additional efforts to develop databases for tracking fish kills, as well as more attempts to publish fish kill studies in the peer-reviewed literature. The recommendations that we provide will advance our ability to identify fish kill causes, and consequently allow us to implement preventative measures to reduce the frequency and magnitude of fish kills worldwide. [ABSTRACT FROM AUTHOR]