Sepsis, acute lung injury, and ARDS contribute substantially to the expanding burden of critical illness within our ICUs. Each of these processes is characterized by a myriad of injurious events, including apoptosis, microvascular dysfunction, abnormal coagulation, and dysregulated host immunity. Only recently have platelets—long considered merely effectors of thrombosis—been implicated in inflammatory conditions and the pathobiology of these disease processes. A growing body of evidence suggests a prominent role for maladaptive platelet activation and aggregation during sepsis and ARDS and has begun to underscore the pluripotential influence of platelets on outcomes in critical illness. Not only do platelets enhance vascular injury through thrombotic mechanisms but also appear to help orchestrate pathologic immune responses and are pivotal players in facilitating leukocyte recruitment to vulnerable tissue. These events contribute to the organ damage and poor patient outcomes that still plague the care of these high-risk individuals. An understanding of the role of platelets in critical illness also highlights the potential for both the development of risk stratification schema and the use of novel, targeted therapies that might alter the natural history of sepsis, acute lung injury, and ARDS. Future studies of adenosine, platelet polyphosphates, and the platelet transcriptome/proteome also should add considerably to our ability to unravel the mysteries of the versatile platelet.