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Marine invertebrate mass mortality events (MMEs) threaten biodiversity and have the potential to catastrophically alter ecosystem structure. A proximal question around acute MMEs is their etiologies and/or environmental drivers. Establishing a robust cause of mortality is challenging in marine habitats due to the complexity of the interactions among species and the free dispersal of microorganisms from surrounding waters to metazoan microbiomes. The 2013–2014 sea star wasting disease (SSWD) MME in the northeast Pacific Ocean highlights the difficulty in establishing responsible agents. In less than a year of scientific investigation, investigators identified a candidate agent and provided at the time convincing data of pathogenic and transmissible disease. However, later investigation failed to support the initial results, and critical retrospective analyses of experimental procedures and reinterpretation of early findings disbanded any candidate agent. Despite the circuitous path that the investigation and understanding of SSWD have taken, lessons learned from the initial investigation—improving on approaches that led to misinterpretation—have been successfully applied to the 2022Diadema antillaruminvestigation. In this review, we outline the history of the initial SSWD investigation, examine how early exploration led to spurious interpretations, summarize the lessons learned, provide recommendations for future work in other systems, and examine potential links between the SSWD event and theDiadema antillarumMME.