The acid-sensing ion channels (ASICs) are voltage-independent ion channels activated by acidic extracellular pH. ASICs play a role in sensory transduction, behavior, and acidotoxic neuronal death which occurs during stroke and ischemia. During these conditions, the extracellular concentration of sulfhydryl reducing agents increases. We used perforated patch-clamp to analyze the impact of sulfhydryls on H⁺-gated currents from CHO cells expressing ASIC subunits and native mouse hippocampal neurons. We found that all ASICs were potentiated by dithiothreitol (DTT). Human ASIC1a currents activated by pH 6.5 were increased almost two fold by DTT and glutathione. DTT shifted the pH dose-response of hASIC1a toward more neutral pH (pH_0.5 from 6.54 to 6.69) and slowed channel desensitization. We found that the effect of DTT on hASIC1a was mimicked by the metal chelator TPEN, and the addition of DTT in the presence of TPEN did not result in further increase in current amplitude. These results suggest that the effect of DTT on hASIC1a is due to relief of tonic inhibition by transition metal ions. Similar results were found for ASIC3 although DTT potentiation of ASIC1b was more complex. We found that all ASICs examined remained potentiated following the removal of DTT. This effect was reversed by the oxidizing agent DTNB in hASIC1a supporting the hypothesis that DTT also impacts ASICs via a redox sensitive site. Thus, sulfhydryl compounds potentiate H⁺-gated currents via two mechanisms, metal chelation and redox modulation of target amino acids.