The concepts underlying the clinical use of the anion gap (AG) and those disorders associated with its alteration are reviewed. A substantial increase in the AG usually indicates the presence of a metabolic acidosis, unless large doses of certain antibiotics or sodium salts of organic acids are being used. The etiology, pathogenesis and diagnosis of high AG metabolic acidoses are discussed. Stress is placed upon the utility of the AG in defining the cause of the acidosis, and as a guide to therapy in certain organic acidoses. A decrease in the normal AG occurs in dilutional states, hypoalbuminemia, hypercalcemia, hypermagnesemia, hypernatremia, diseases associated with hyperviscosity, bromide intoxication, and in certain paraproteinemias. The important clue provided by a low or negative AG in the diagnosis of certain of these life-threatening disorders is emphasized.