Advances in therapy strategies, due to improved understanding of resuscitation, enhanced wound coverage, better support of hypermetabolic response to injury, more appropriate infection control, and improved treatment of inhalation injury, based on better understanding of the pathophysiologic responses to burn injury have further improved the clinical outcome of this unique patient population over the past years [1]. This chapter describes the present understanding of the pathophysiology of a burn injury including both the local and systemic responses, focusing on the many facets of organ and systemic effects directly resulting from hypovolemia and circulating mediators following burn trauma.