Acute pain from episodic vaso-occlusion (VOC) spans the lifespan of almost everyone with sickle cell disease (SCD), while additional chronic pain develops in susceptible individuals in early adolescences. Frequent acute pain with chronic pain causes significant physical and psychological morbidity, and frequent healthcare utilization. Available pharmacologic therapies reduce acute pain frequency but few evidence-based therapies are available for chronic pain. An extensive PubMed literature search was performed with appropriate search criteria. The pathophysiology of acute pain from VOC in SCD is very complex with many events subsequent to sickle polymer formation. Sensitization of pain pathways and alterations of brain networks contributes to the experience of chronic pain. Numerous therapies targeting putative VOC mechanisms are in clinical trials, and show considerable promise. Alternative analgesic treatments for acute and chronic pain have been examined in small patient cohorts, but formal clinical trials are lacking. Childhood is likely a critical window for prevention of acute and later chronic pain. New multimodal analgesic therapies are needed, particularly for chronic pain, and should be examined in clinical trials. Given the multifactorial nature of both pain and VOC, simultaneously targeting multiple mechanisms may be the optimal approach for effective preventive therapies.