Declines of freshwater mussel (order Unionida) populations worldwide are attributed to habitat degradation, pollution, and invasive species, among other factors. However, these purported causes do not fully explain the enigmatic decline and large-scale die-offs of mussels that have occurred in assumedly “healthy” streams across a wide geographic region. The roles of the microbiota and pathogens in mussel health has been understudied, and, as a result, few references exist to compare the microbiota of healthy mussels to that of stressed or dying mussels. Captive propagation and stocking programs have expanded across the globe without standard diagnostic protocols to assess health or potential diseases in hatchery-reared or wild stocks. Introduction of nonindigenous species, contaminants of emerging concern and anthropogenic climate change could adversely alter underlying variables that support mussel health such as nutrient and microbial composition, in addition to increased risk for outbreaks of opportunistic disease and emergent diseases in freshwater mussel populations. We suggest a coordinated, collaborative, and multidisciplinary effort to advance methods for assessing freshwater mussel health. We identify research and resources needed to answer central questions surrounding mussel health including identifying potential agents of disease, defining clinical signs of declining condition, refining stress-specific biomarkers for health assessment, and developing protocols specific for mussels.