Computational studies of the solution-phase mechanism of nucleophilic substitution at sulfur in disulfides with explicit water representation indicate that the pathway is dependent on the substituent on the sulfur under attack. B3LYP/6-31+G* optimizations for prototype thiolate-disulfide exchange reactions were performed including one to four explicit water molecules, followed by single-point free energy calculations with B3LYP/ 6-31+G* and the polarized continuum model (PCM). The solution-phase mechanism is the addition-elimination mechanism when the sulfur under attack bears a hydrogen, while the S(N)2 mechanism is predicted when the sulfur substituent is a methyl group.