Chloride represents—quantitatively—the most prevalent, negatively charged, strong plasma electrolyte. Control of chloride concentration is a probable major mechanism for regulating the body’s acid–base balance and for maintaining homeostasis of the entire internal environment. The difference between the concentrations of chloride and sodium constitutes the major contributor to the strong ion difference (SID); SID is the key pH regulator in the body, according to the physicochemical approach. Hyperchloraemia resulting from either underlying diseases or medical interventions is common in intensive care units. Recent studies have demonstrated the importance of hyperchloraemia in metabolic acidosis and in other pathophysiological disorders present in sepsis. The aim of this narrative review is to present the current knowledge about the effects of hyperchloraemia, in relation to the underlying pathophysiology, in septic patients.