This narrative review aims to highlight the current paradigm on pain management in sickle cell vaso-occlusive crisis. It specifically examines the pathophysiologic mechanisms of sickle cell pain as well as the pharmacologic and nonpharmacologic methods of pain management. Recurrent painful episodes constitute the major morbidity in sickle cell disease (SCD). While adolescents and young adults experience mostly acute episodic nociceptive pain, it is now recognized that a significant number of adult patients develop chronic neuropathic and centralized pain. In fact, current evidence points to an age-dependent increase in the frequency of SCD patients with chronic pain. Management of disease-related pain should be based on its pathophysiologic mechanisms instead of using recommendations from other non-SCD pain syndromes. Pain management in vaso-occlusive crisis is complex and requires multiple interventions such as pharmacologic, nonpharmacologic, and preventive therapeutic interventions. Pharmacologic treatment involves the use of non-opioid and opioid analgesics, and adjuvants – either singly or in combination – depending on the severity of pain. The basic approach is to treat SCD pain symptomatically with escalating doses of non-opioid and opioid analgesics. Given the moderate-to-severe nature of the pain usually experienced in this form of SCD crisis, opioids form the bedrock of pharmacologic treatment. Multimodal analgesia and structured, individualized analgesic regimen appear more effective in achieving better treatment outcomes. Although the current evidence is still limited on the supportive role of cognitive behavioral therapy in pain management, this nonpharmacologic approach is reportedly effective, but needs further exploration as a possible adjunct in analgesia.