Exceptionally large kinetic isotope effects are observed in the proton-transfer reaction of the carbon acid 4-nitrophenylnitromethane with the strong nitrogen base tetramethylguanidine (TMG) in solvents of low polarity such as toluene; values of k^H/k^D up to ∼50 and of A^D/A^H up to ∼100 have been reported. The volume of activation has been determined in several of these solvents and shows only small variations. In solvents of higher polarity, such as THF, dichloromethane or acetonitrile, the isotope effects are smaller. With tertiary amines in place of TMG as base, the isotope effects show a similar solvent-dependence but are all smaller. These effects are interpreted in terms of tunnelling. The factors influencing the tunnelling correction are discussed : (i) the dimensions of the barrier to proton-transfer (ii) possible changes of configuration in the reactant molecules, and (iii) solvent motions coupled to the proton-transfer. The data on other reactions exhibiting tunnelling are considered in the light of this discussion.