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Mussels (Bivalve: Mytilidae) have adapted to various habitats, from fresh water to the deep sea. To understand their adaptive characteristics in different habitats, particularly in the bathymodiolin mussels in deep‐sea chemosynthetic ecosystems, we conducted a comparative transcriptomic analysis between deep‐sea bathymodiolin mussels and their shallow‐water relatives. A number of gene families related to stress responses were shared across all mussels, without specific or significantly expanded families in deep‐sea species, indicating that all mussels are capable of adapting to diverse harsh environments, but that different members of the same gene family may be preferentially utilized by different species. One of the most extraordinary trait of bathymodiolin mussels is their endosymbiosis. Lineage‐specific and positively selected TLRs and highly expressed C1QDC proteins were identified in the gills of the …