This brief review describes the main physicochemical factors that contribute to increases in intracellular hydrogen ion concentration ([H+]i) in mammalian skeletal muscle during high intensity exercise. High intensity exercise results in changes in the three main independent physicochemical variables: PCO2, the strong ion difference ([SID]), and total concentration of weak acids and bases ([Atot]), within the intracellular fluid compartment of contracting muscle that result in increased [H+]i. The decrease in [SID] contributes 62% to the increase in [H+]i, due to decreased [K+]i and increased [lactate]i; the decrease in phosphocreatine ([PCr2-]i) exerts an alkalinizing effect. The increase in [Atot], resulting primarily from increases in inorganic phosphate and creatine as a result of PCr2- breakdown, contributes 19% to the increase in [H+]i. An increase in the apparent proton dissociation constant (KA) for [Atot] contributes 7% to the increase in [H+]i. PCO2 is a relatively poor effector of changes in [H+]i, such that a 50-mmHg increase in PCO2 contributes only 12% to the increase in [H+]i during high intensity exercise.