Acute lung injury (ALI) is a common syndrome associated with a high mortality rate. Better understanding of the pathophysiology of acute lung injury and progress in supportive care and mechanical ventilation have led to slightly improved clinical outcomes. New evidence shows that the interplay between platelets, leukocytes and endothelial cells is critical in the pathogenesis of ALI. Key molecules involved in this interaction include P-selectin and the eicosanoid thromboxane A2 (TXA2), suggesting potential new targets for pharmacological intervention. In this review, we summarize the aspects of the interactions between platelets, leukocytes, and endothelial cells that are relevant for the pathogenesis of ALI.