The swelling-activated chloride current, commonly referred to as ICl,swell, is an outwardly-rectifying anion current that plays an important role in cell volume regulation, among other capacities. Despite several decades of research, the molecular identity of the channel responsible for this chloride current remains controversial. Recent indications that key endogenous sulfhydryl groups are capable of modifying the current led us to assess the effects of several divalent cations, including zinc, on ICl,swell. Zinc is known to tightly associate with sulfhydryl groups such as in zinc finger proteins. We found that extracellular zinc irreversibly inhibited ICl,swell at a site downstream in the signaling cascade. Moreover, zinc blocking kinetics were voltage dependent, suggesting interaction with a site within the electric field, across the pore of the channel responsible for ICl,swell. The importance of sulfhydryl groups was confirmed by demonstrating irreversible block by N-ethylmaleimide, a sulfhydryl alkylating reagent. In contrast, nickel failed to block ICl,swell, and as noted in previous studies, cadmium preferentially blocked the time-dependent component of ICl,swell. These data confirm the importance of sulfhydryl groups in the function of ICl,swell. Moreover, by demonstrating the voltage-dependence of block, the data strongly suggest the critical sulfhydryl group is within the channel pore. These biophysical characteristics of native ICl,swell are markers that should be recapitulated in expressed proteins claimed to be responsible for ICl,swell.