Hemorrhagic shock is the leading cause of death in civilian and military trauma. Effective hemorrhage control and optimal resuscitation are the main goals in the management of severely injured patients. This article addresses the changing trends in fluid resuscitation in regards to who, when, and how. Much of these changing trends are caused by the recognition that the current method of resuscitation with crystalloid fluids may not be optimal and may even have detrimental consequences. This article summarizes a number of studies that have evaluated the cellular toxicities of commonly used resuscitation fluids, to highlight the need for the development of new fluids.