Sickle cell disease (SCD) is the most common inherited red blood cell (RBC) disorder worldwide, resulting in chronic hemolytic anemia, vaso-occlusion, tissue hypoxia, and ultimately end organ damage. The hallmark of the disease is manifested by vaso-occlusive crisis (VOC) resulting in acute on chronic pain, and the most common cause for presentation to the emergency department and hospital admission. The management of pain for patients with SCD in the U.S. has historically been socially and politically complex with most patients experiencing pain on a daily basis but not seeking immediate medical attention. The pathophysiology of acute and chronic pain in SCD is multifactorial and complex. Here, we describe factors contributing to acute and chronic pain in SCD and management strategies.