Patients with sickle cell disease (SCD) exhibit high plasma levels of markers of thrombin generation, depletion of natural anticoagulant proteins, abnormal activation of the fibrinolytic system, and increased tissue factor expression, even in the non-crisis steady state. In addition, platelets and other cellular elements are chronically activated in the non-crisis state. Despite an abundance of evidence for coagulation and platelet activation, it remains uncertain whether these changes contribute to the pathophysiology of SCD or are, rather, simple epiphenomena. With the occurrence of macrovascular thrombotic complications in SCD, as well as the recognition that soluble CD40 ligand is biologically active in SCD, coagulation and platelet activation may indeed play a role in SCD pathophysiology. Defining a role for hypercoagulability in SCD requires further understanding of its pathogenesis. Furthermore, the conduct of well-controlled clinical trials using anticoagulants and antiplatelet agents and using a variety of clinical endpoints is warranted.