The pain of vaso-occlusive crisis in patients with sickle cell disease is excruciating, incapacitating, and sometimes refractory to even the most advanced analgesic treatments. A comprehensive, multimodal approach to therapy that includes education, cognitive therapies, anti-inflammatory drugs, opioids, and psychostimulant adjuvant drugs has been presented. Until a cure for the underlying disease is found, these are the best approaches available. The authors hope that future research will find even better modalities of analgesic care.