Loss of freshwater mollusk populations nationally has prompted the use of these species in establishing USEPA water quality criteria (WQC). The objectives of this study were to determine the sensitivity (EC₅₀) of 5 at-risk mollusk species endemic to the Mobile River Basin to chloride, potassium, nickel, and zinc. Villosa nebulosa (Alabama Rainbow) was the only species evaluated in the study with an EC₅₀ value included under current WQC for chloride and nickel. All species in the current study were more sensitive to potassium than other mollusk species previously tested, although there is currently no established WQC for that contaminant. For zinc, all species but Leptoxis ampla (Round Rocksnail) had EC₅₀ values included under existing criteria. Results suggest current WQC may be insufficient for basins containing localized endemic species in a relatively small geographical space, such as the Mobile River Basin. We urge broader testing of highly regionalized aquatic species to aid in establishing national WQC.