Attempts to decipher the life cycle of Haplosporidium nelsoni began almost immediately after it was identified as the pathogen causing MSX disease in eastern oysters, Crassostrea virginica. But transmission experiments failed and the spore stage, characteristic of haplosporidans, was extremely rare. Researchers concluded that another host was involved: an intermediate host in which part of the life cycle was produced, or—if the oyster was an accidental host—an alternate host that produces infective elements. A later finding that spores were found more often in spat (<1 y old) than in adults revived the idea of direct transmission between oysters. The new findings and the availability of molecular diagnostics led us to revive life cycle investigations. Over several years, oyster spat were examined for spores and searched for H. nelsoni in potential non-oyster hosts using both histological and polymerase chain reaction (PCR) methodologies. Although spores occurred in a high proportion of spat with advanced infections, it was concluded that they were unlikely to be a principal source of infective elements because naïve oysters used as sentinels to assess infection pressure became highly infected even after native oysters developed resistance, and infected spat could no longer be found. A histological survey of zooplankton and small bivalves in Delaware Bay found few recognizable parasites and nothing resembling a haplosporidan. A subsequent PCR study of water, sediment, and macroinvertebrates from Chesapeake, Delaware, and Oyster bays resulted in many positive samples, but in situ hybridization failed to identify any recognizable structures. PCR analysis of potential intermediate hosts for other molluscan pathogens has also resulted in many species yielding positive results but required in situ hybridization to verify infections. It is suggested that any future search for a nonoyster host of H. nelsoni be conducted in a relatively confined system and/or target specific phyla, strategies that have been successful in other life cycle studies. It is noted that candidate phyla could include those known to host haplosporidans and species whose abundance or distribution may have changed in concert with outbreaks of MSX disease in the northeastern United States in recent years.