When approaching the analysis of disorders of acid-base balance, physical-chemists, physiologists, and clinicians, tend to focus on different aspects of the relevant phenomenology. The physical-chemist focuses on a quantitative understanding of proton hydration and aqueous proton transfer reactions that alter the acidity of a given solution. The physiologist focuses on molecular, cellular, and whole organ, transport processes that modulate the acidity of a given body fluid compartment. The clinician emphasizes the diagnosis, clinical causes, and most appropriate treatment of acid-base disturbances. Historically, two different conceptual frameworks have evolved among clinicians and physiologists for interpreting acid-base phenomena. The traditional or bicarbonate-centered framework relies quantitatively on the Henderson-Hasselbalch (H-H) equation whereas the Stewart or strong ion approach utilizes either the original Stewart equation or its simplified version derived by Constable. In this review, the concepts underlying the bicarbonate-centered and Stewart formulations are analyzed in detail emphasizing the differences in how each approach characterizes acid-base phenomenology at the molecular level, tissue level, and in the clinical sphere. A quantitative comparison of the equations that are currently used in the literature to calculate [H⁺] is included in order to clear up some of the misconceptions that currently exist in this area. Our analysis demonstrates that: 1) while the principle of electroneutrality plays a central role in the strong ion formulation, electroneutrality per se does not dictate a specific [H⁺] and 2) the strong ion and bicarbonate-centered approaches are quantitatively identical; however, only the bicarbonate-centered approach reflects the underlying mechanistic acid-base phenomenology.