The pathophysiology of burns is similar in several aspects to the hypermetabolic response, complex, and formidable. Pathophysiology involves not only the alterations in the skin with the thermal injury, but it involves all organs, and ultimately is connected also to the hypermetabolic response. This chapter delineates the pathophysiologic changes on an organ basis, and tissue basis, and to a certain extent systemic as well as immune responses. This will give the reader a better understanding on the changes that occur after a burn, how to treat and alleviate this response, and lastly how to improve the outcomes.