Every year, the number of people using commercial aircraft is estimated at two billion, and more than 300 million people take long-haul flights. Sickle cell patients may be at risk during the air journey because significant hypobaric hypoxia may occur at cruising altitude. This literature review reports complications related to air travel such as painful crises, serious spleen complications (spleen infarcts) requiring a splenectomy, or even sudden death. Prevention of these complications includes environmental protection (maintaining pressure inside the aircraft cabin in a hypobaric condition) and individual prophylaxis (general recommendations for all travelers and specific measures for sickle-cell patients). In order to assess complications associated with air travel in sickle-cell patients, an assessment of their ability to fly is necessary. In addition, the flight fitness assessment identifies patients who will need additional oxygen during flight. When prescribed by the passenger’s physician, additional oxygen is provided by most airlines. Knowing these elements makes it possible to anticipate problems and provide appropriate responses to patients.