Recent advances in endotoxin biochemistry, cell biology, and immunopathology are reviewed. Discussion is focused on the endotoxin-unresponsive C3H/HeJ mouse and the contributions the studies of this mouse have made to current concepts of the mechanisms of endotoxin action. The extension of the observations documented with this experimental model provide a firm foundation for productive future research into the precise role of bacterial endotoxins in the protection against, and exacerbation of, gram-negative bacterial sepsis.