Vaso-occlusive crises are one of the most debilitating features of sickle cell disease. There appears to be no standardization of care for adults with pain crisis, and some commonly utilized regimens, such as those employing intramuscular meperidine, are pharmacologically unsound. Parenteral narcotic use may be associated with respiratory compromise acutely and with dependence over the long term, but nonopioid preparations are often unsatisfactory in relieving pain. We have recently enjoyed success with a combination of a parenteral nonsteroidal anti-inflammatory medication and an oral tricyclic antidepressant. We report four representative cases and review the salient points of the management of pain crisis in adult patients in the emergency department.