Secondary peritonitis continues to cause high morbidity and mortality despite improvements in medical and surgical therapy. This review combines data from published literature, focusing on molecular patterns of inflammation in pathophysiology and prognosis during peritonitis. Orchestration of the innate immune response is essential. To clear the microbial infection, activation and attraction of leukocytes are essential and beneficial, just like the expression of inflammatory cytokines. Exaggeration of these inflammatory systems leads to tissue damage and organ failure. Nonsurvivors have increased proinflammation, complement activation, coagulation, and chemotaxis. In these patients, anti-inflammatory systems are decreased in blood and lungs, whereas the abdominal compartment shows decreased neutrophil activation and decreased or stationary chemokine and cytokine levels. A later down-regulation of proinflammatory mediators with concomitant overexpression of anti-inflammatory mediators leads to immunoparalysis and failure to clear residual bacterial load, resulting in the occurrence of superimposed infections. Thus, in patients with adverse outcome, the inflammatory reaction is no longer contained within the abdomen, and the inflammatory response has shifted to other compartments. For the understanding of the host response to secondary peritonitis, it is essential to realize that the defense systems presumably are expressed differently and, in part, autonomously in different compartments.