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We discuss the importance of the composition of intravenous crystalloid solutions. On the basis of current physiologic principles, evidence from basic science and clinical experiments, recent observational studies, and clinical trials, we conclude that the ‘ideal crystalloid’ depends on clinical context. We make recommendations on solutions that may be used during critical illness, major surgery, and certain clinical situations.The routine use of solutions with a supraphysiologic chloride content and a low strong ion difference (SID), such as isotonic saline solution, may be associated with adverse outcomes, especially among critically ill patients. On the contrary, solutions with a physiologic chloride content and a ‘balanced’ electrolyte composition (SID closer to plasma) may improve the likelihood of survival. The distribution of different types of crystalloids across traditional ‘body compartments’ is a function of osmolality of the fluid infused relative to plasma, integrity of the glycocalyx, and the hemodynamic/‘volume’ state of the patient. During critical illness, the routine administration of colloids may offer no clinical benefits compared with the use of crystalloids.Crystalloids, like other types of intravenous fluids, are drugs with important effects on clinical outcomes that may be mediated by osmolality, chloride content, and SID.