Ebselen and other small organoselenium compounds mimic the activity of glutathione peroxidase (GPx) and have been proposed for treatment and prevention of cancer and other chronic conditions associated with high concentrations of reactive oxygen species. Computational modeling of the reactivity of these species is complicated by proton exchanges associated with the mechanistic steps. Modeling of the GPx-like catalytic cycle of ebselen and Back-style GPx mimics has been accomplished using DFT and solvent-assisted proton exchange (SAPE). SAPE is a modeling technique that mimics solvent participation in proton transfer associated with chemical reaction. Within this method, explicit water molecules allow relay of a proton from the site of protonation in the reactant and to that in the product. The activation barriers obtained by SAPE for the these mechanisms fall within the limits expected for a catalytic system at physiological temperatures and are significantly lower than studies which force direct proton transfer. Strategies for modeling other organoselenium chemotherapeutics are also discussed.