Neutrophil-mediated tissue injury (NMTI) is a prominent mechanism of host autodestruction. It is defined by a sequence of events including neutrophil adherence and sequestration, diapedesis, activation, and secretion of toxic compounds. Knowledge of this sequence is valuable because it outlines points at which intervention may be sought. A limitation of these studies comes in the misunderstanding and misapplication of the tests used to analyze these events. We now realize that neutrophil adherence, sequestration, diapedesis, and secretion of toxic compounds can each occur alone without promoting generalized tissue injury. NMTI is a normally localized process that has gone systemically awry. Influencing this system must be selective and controlled because the inflammatory system is a critical component of host defense. As we gain insight into the pathophysiology of NMTI, we hope to find new avenues for therapeutic intervention in critical care.