The effects of ten cations and fifteen anions on the excitability of the squid giant axon were studied. The method of intracellular perfusion used in these investigations is described in detail. Empirical criteria were established for evaluating the relative favorability of any salt solution for maintaining the normal excitability of the membrane of the axon. It was found that both cations and anions could be ordered in sequences of relative favorability, which are directly related to the classic lyotropic sequences found for protein macromolecules and in colloid chemistry in general. The effects of concentration, salt mixtures, non-electrolyte carriers, enzymes, metabolic inhibitors, pH, and external media were also studied. The results are interpreted in terms of current concepts of the interactions between water structure, charged macromolecules, and their ionic environments. A macromolecular approach is given to the physicochemical nature of the "two stable states" of the excitable membrane, to describe the time-dependent potential changes observed.