Acute pain is the hallmark of sickle cell disease and is the most common cause of hospital admissions. Tissue damage due to vaso-occlusion releases numerous inflammatory mediators that initiate the transmission of painful stimuli that culminate in the perception of pain. The acute sickle cell painful crisis evolves along four phases. Each phase is coupled with changes in certain markers of the disease. Hospital readmission occurs within 1 week in about 16% of discharged patients and within 1 month in about 50% of discharged patients. Failure to treat acute pain aggressively may lead to chronic pain syndrome which, in turn, initiates neuropathic pain. Management of sickle pain is primarily pharmacological in nature and opioids are the analgesics used most often. Adverse effects of opioids include histaminergic, excitatory, dopaminergic and proserotonergic effects. Cellular and molecular mechanisms of opioids explain individual differences among patients and justify the use of individualized treatment plans.