During the centuries the pathophysiological concept of illness underwent drastic changes, depending on medical discoveries and religious belief. There is evidences of surgical practice in Mesopotamia, Egypt, and Greece 2000 years B.C., but we have to wait the Roman Empire with Celso, Galeno, and most of all Asclepiade and Temisone to appreciate the endeavor to rationally understand diseases as an alteration among different body constituents and not only as divine will. During the Middle Ages, when medicine was disputed by clergy, Ugo and Teodorico Borgognone perceived by intuition the problem of sepsis in patient recovery. This problem was cleared up six centuries later by Semmelweis with his antisepsis. Discoveries of blood circulation, hemostasis, anesthesia, and antisepsis in the 17th and 19th centuries permitted better disease management and have promoted, since the 1950s, pathophysiology as an autonomous discipline. Now pathophysiological mechanisms are used for comprehension of several diseases, such as gallstone formation, peptic ulcers, cranial trauma, cardiovascular abnormalities, and many others, to suggest to us which are the better surgical or clinical trials to realize, while observing caution about their limits and consequences. By a multidisciplinary approach involving surgeons, physiologists, biologists, and physicians, we are able to facilitate patient recovery and to perform modern, scientific, high-quality disease management.