Oxidants play a key role in disease processes, particularly in the detrimental mechanisms leading to tissue damage in certain forms of acute lung injury. A number of mediators contribute to the pathologic response in ARDS, SIRS or hyperoxia-induced pulmonary damage. One of the most important detrimental factors is the generation and activation of highly reactive oxygen species which are leading factors implicated in the process of tissue damage. N-acetylcysteine (NAC) is a free radical scavenger and might access the endothelial cell thus increasing intracellular glutathione (GSH) stores. Different studies have demonstrated that NAC might be a promising compound either for the prevention or the treatment of acute lung damages such as ARDS. However, the true beneficial effect so far reported in several clinical and experimental studies contrasts with some contradictory and intriguing aspects, probably because the significance of a direct in vivo antioxidative effect of this compound remains to be established in humans. Thus, the mode of action of NAC may not be the same in different pathologies and clinical situations. More research into the mechanisms of action of this unique xenobiotic substance may offer a clue for elucidating these controversies.