The analgesic approach to sickle cell vaso-occlusive crisis (VOC) depends on the episode's severity, which can vary between patients and even within individual's successive presentations. An improving understanding of VOC pathophysiology is outlined by a broad and informative literature. The first interventions in managing VOC pain are supportive therapies. Recommendations to decrease VOC duration by administration of oxygen and IV fluids are physiologically well grounded, and such interventions form part of nearly all VOC care protocols. Mild VOC pain can be treated with oral acetaminophen or NSAIDs. Administered by a variety of methods, opioids can safely and effectively relieve VOC pain. Orally administered controlled-release preparations of morphine have been used with success in VOC, as long as they are supplemented with additional medication as needed. The patient controlled analgesia (PCA) technology is of high potential utility in the ED management of VOC. The role of corticosteroids in treating VOC continues to evolve. Data of primarily historical interest suggest potential utility of hydrocortisone monotherapy.