At this point in time several major problems must be solved before the results of acid-base reactions can be predicted, even moderately well in given solvent. Theoretically, it would be desireable to be able to estimate, on the basis of energy, the intrinsic acidity of acids as well as the basicity of substances with which acids react under practical circumstances, whether the latter is a solvent or a reference base. The available data suggest that hydrogen-containing substances exhibit characteristic protonic acidities which can be manifested, more or less, in different solvents. The ionization of a substance to form protons in the gas phase is a suggested unambiguous measure of its inherent acid strength, but sufficient thermochemical data are not available to estimate the extents of such processes for a series of related compounds. The gas phase ionization can be related to the ionization process in solution by considering the solvation of the molecular form of the acid, its conjugate base, the proton. In general, little is known of the fundamental nature of the solvation process for molecular acids and their conjugate ions, although estimates of the energy of solvation of the proton in a series of solvents, or the energy required to transfer a proton between two solvents, have been made. Perhaps the most difficult of the theoretical areas that need to be addressed is a detailed consideration of the nature of electrostatic solute-solvent interactions, as well as the more specific hydrogen-bonded interactions. Such interactions must be better understood from a theoretical standpoint before a priori decisions can be made concerning which factors, if any, will determine the course of an acid-base reaction.