Activation of the coagulation cascade resulting in alveolar fibrin deposition is recognized as a hallmark of acute lung injury (ALI). Anticoagulant treatment with recombinant human activated protein C (rhAPC) appears promising, because - like in sepsis - there is a deficiency of protein C in ALI, which is correlated with poor outcome in both syndromes. Recently in Critical Care, Waerhaug and colleagues confirmed the beneficial effects of rhAPC on pulmonary function in ovine endotoxin-induced ALI. Notably, the authors reported no differences in hemorrhage in histologic analyses between rhAPC-treated and untreated animals. However, a recently reported randomized, placebo-controlled, multicenter trial in ALI patients without severe sepsis failed to identify any differences in the number of ventilator-free days or 60 day-mortality between the rhAPC and placebo group. In addition to (or perhaps because of) the complex pathogenesis, the discrepancy between clinical and experimental results in ALI is another common feature with sepsis. The future challenge will be to transfer our theoretical knowledge adequately into daily clinical practice. Anticoagulant therapy might be a useful tool in the treatment of ALI; however the proper operating instruction remains to be defined.