We present a DFT study on the reactivity of an alkoxide and a thiolate toward the neutral and all ionic forms of arsenate and phosphate. The isolated neutral, mono-, di-, and trianionic arsenate/phosphate (electrophiles) and thiolate/methanolate (nucleophiles) species are used as model systems of reacting partners in the enzymatic reactions catalyzed by arsenate reductase and phosphatase. The onset of the displacement reaction at the electrophilic center by the attacking nucleophile is described by the DFT descriptor local softness, applied in a HSAB context. The instability of multiply charged anions in gas phase necessitates the use of a solvent model with an appropriate dielectric constant mimicking the enzymatic environment. Gas-phase and solvent-reactivity studies of isolated compounds indicate that the nucleophilic attack of a thiolate during the first catalysis step of arsenate reductase (ArsC) and low molecular weight phosphatase (LMWPTPase) preferably occurs via the dianionic arsenate and phosphate. This computational approach confirms and supplements earlier experimental data.