The epithelial sodium channel (ENaC) is regulated by multiple extracellular stimuli, including shear stress. Previous studies suggest that the extracellular finger domains of ENaC α and γ subunits contain allosteric regulatory modules. However, the role of the finger domain in the shear stress response is unknown. We examined whether mutations of specific residues in the finger domain of the α subunit altered the response of channels to shear stress. We observed that Trp substitutions at multiple sites within the tract αLys-250-αLeu-290 altered the magnitude or kinetics of channel activation by shear stress. Consistent with these findings, deletion of two predicted peripheral β strands (αIle-251-αTyr-268) led to slower channel activation by shear stress, suggesting that these structures participate in the shear stress response. The effects of mutations on the shear stress response did not correlate with their effects on allosteric Na(+) inhibition (i.e. Na(+) self-inhibition), indicating a divergence within the finger domain regarding mechanisms by which the channel responds to these two external stimuli. This result contrasts with well correlated effects we previously observed at sites near the extracellular mouth of the pore, suggesting mechanistic convergence in proximity to the pore. Our results suggest that the finger domain has an important role in the modulation of channel activity in response to shear stress.