Despite intensive research, brain tumors remain among the most difficult type of malignancies to treat, due largely to their diffusely invasive nature and the associated difficulty of adequate surgical resection. In order to migrate through the brain parenchyma and to proliferate, glioma cells must be capable of large changes in shape and volume. We have previously reported that glioma cells express an amiloride-and psalmotoxin-sensitive cation conductance that is not found in normal human astrocytes. In the present study we investigated the potential role of this ion channel to mediate regulatory volume increase (RVI) in glioma cells. We found that the ability of the cells to volume regulate subsequent to cell shrinkage by hyperosmolar solutions was abolished both by amiloride and by psalmotoxin 1. This toxin is thought to be a specific peptide inhibitor of ASIC1, a member of the Deg/ENaC super family of cation channels. We have previously shown this toxin to be an effective blocker of the glioma cation conductance. Our data suggest that one potential role for this conductance may be to restore cell volume during the cells progression thorough the cell cycle and while the tumor cell migrates within the interstices of the brain.