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Secondary peritonitis accounts for 1% of urgent or emergent hospital admissions and is the second leading cause of sepsis in patients in intensive care units globally. Overall mortality is 6%, but mortality rises to 35% in patients who develop severe sepsis. Despite the dramatic growth in the availability and use of imaging and laboratory tests, the rapid diagnosis and early management of peritonitis remains a challenge for physicians in emergency medicine, surgery, and critical care. In this article, we review the pathophysiology of peritonitis and its potential progression to sepsis, discuss the utility and limitations of the physical examination and laboratory and radiographic tests, and present a paradigm for the management of secondary peritonitis.