The pain of vaso-occlusive crisis in sickle cell disease is excruciating, incapacitating, and at times, refractory to even the most advanced analgesic treatments. The authors discuss the pathophysiology of sickle cell disease, define acute and chronic pain syndromes in sickle cell disease, and outline barriers to effective care. A comprehensive, multimodal approach to therapy that includes education, cognitive therapies, anti-inflammatory drugs, opioids, and psychostimulant adjuvant drugs is also provided.