This chapter mainly focuses on the sickle cell disease. Sickle cell disease is prevalent in the Middle East, Mediterranean, Africa, and India. It results from a single gene mutation within the beta chain of hemoglobin A. This mutation results in the formation of hemoglobin S, which in the presence of low oxygen saturation, causes sickling of red blood cells and occlusion of blood vessels. A detailed history and physical examination must be obtained prior to treatment. Evaluation of the patient’s baseline pain and the frequency and severity of pain crises must be obtained. The majority of pain episodes can be managed with nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and mild opioids.