Although peritonitis has been recognized as a common and complex disease entity since ancient times, the true understanding and pathophysiology, as well as treatment of peritonitis, continue to plague surgeons and physicians. The clinical course and outcome of peritonitis is dependent upon the struggle between the quantity and virulence of the pathogen and host's physiologic reserve, including the ensuing inflammatory response. The current multimodality treatment of intraabdominal infections is based upon the fundamental principles established by Polk in 1979: surgical source control, fluid resuscitation, adequate nutrition, support of failing organ systems, and antibiotics. Although dramatic advances have been made in the pharmacological treatment of intraabdominal infections, mortality for complicated cases remains high. Consequently, future directions in management of peritonitis may require agents that target specific endotoxin receptors, inflammatory signaling molecules, or immunomodulatory moieties.