Venous thromboembolism (VTE) is common in patients with sickle cell disease (SCD). The etiology of increased risk of VTE in SCD patients is multifactorial and is related to both traditional factors and SCD-specific factors. Traditional risk factors such as central venous catheters, frequent hospitalization, orthopedic surgeries for avascular necrosis, and pregnancy may lead to increased incidence of VTE in the SCD population. In addition, SCD itself appears to be a hypercoagulable state, and many SCD-specific factors such as thrombophilic defects, genotype and splenectomy may modify the risk of VTE. SCD complications such as acute chest syndrome and pulmonary hypertension may also be related to VTE. Anticoagulation experts should be aware of these factors to help inform prophylaxis and treatment decisions.