Two types of gas-phase proton transfer reactions were examined with electrospray ionization-generated peptide and protein ions; (i) bases reacting with multiply protonated molecules and (ii) acids reacting with multiply deprotonated molecules. For reactions of type (i) with bases spanning a range of proton affinities, the proton transfer reaction rate was observed to increase with increasing proton affinity of the charge transfer reagent. Proton transfer was not observed for the low proton affinity reagents (ethyl acetate, acetonitrile and water). These studies also qualitatively measured for the first time the temperature dependences for reactions with multiply charged peptides and proteins. Negative temperature dependences were observed for the weaker bases and positive dependences for the stronger bases. A negative temperature dependence was also observed in the reaction of propionic acid with [M – nH]n− ions. Two hypotheses are proposed to explain the data. In the first, negative temperature dependences are attributed to slightly exothermic reactions, while the positive dependences may reflect contributions from a competing clustering pathway, a pathway which could be more dominant with the heavier reagents. Alternatively, the positive temperature dependences may reflect the barrier in the reaction coordinate arising from the repulsion of like-charged ions, while negative temperature dependences could reflect a cluster-mediated reaction in which charge delocalization lowers the barrier to proton transfer. In the latter cases, clustering is invoked with the lower proton affinity reagents because of the higher concentrations employed.