Sepsis and peritonitis remain a serious challenge for surgical patients, despite improvement in surgical therapy and intensive care and the introduction of new powerful antibiotics. Recent in vitro studies revealed the potential of certain antibiotics, e.g. penicillin-binding protein (PBP) 3-specific antibiotics, to cause antibiotic-induced endotoxin release. Other types of antibiotics, e.g., PBP 2-specific antibiotics, were associated with no or less endotoxin release. Further in vitro experiments and investigations in animals support the hypothesis of antibiotic-induced endotoxin release, but there is little clinical evidence. The clinical significance of endotoxin is subject of open dispute with many pro's and contra's. Endotoxin, although an important trigger, may not be the only factor to induce cytokine release, e.g., peptidoglycans were able to stimulate cells to release cytokines. Gram-positive pathogens have gained more importance in clinical sepsis and may not be sufficiently reflected in current clinical studies. The hypothesis that neutralization of endotoxin and pro-inflammatory cytokines is beneficial in sepsis was seriously challenged by the results of recent clinical and experimental studies. The better understanding of mechanisms in endotoxin-induced cell activation and cell, cell-receptor and soluble receptor interactions led to new treatment options. Recent reports on the complex pathogenesis of peritonitis and the detection of pathogen-related factors with intraperitoneal immune response may have implications on clinical studies investigating the potential of new compounds and the effect of antibiotics on endotoxin release. However, only few reports are available on the clinical significance of antibiotic-induced endotoxin release, and association of endotoxin release with pathogens, mortality or alteration of physiological parameters were not observed. With regard to the particulars of these studies, e.g., a small study population or low mortality rate, mortality may not be an ideal outcome parameter for these studies. There is clinical evidence for antibiotic-induced endotoxin release. However, the need for well-designed and performed studies using newly developed monitoring devices in intensive care therapy is obvious.