Pain is a major comorbidity of sickle cell disease (SCD). Patients with SCD may suffer from both acute and chronic pain. Acute pain is caused by recurrent and unpredictable episodes of vaso-occlusive crises (VOC), whereas the exact etiology of chronic pain is still unknown. Opioids are the mainstay for pain treatment, but the opioid epidemic has significantly altered access to prescription opioids and has brought concerns over their long-term use into the forefront, which have negatively impacted the treatment of sickle pain. Opioids remain potent analgesics but growing opioid-phobia has led to the realization of an unmet need to develop non-opioid therapies that can provide relief for severe sickle pain. This realization has contributed to the approval of 3 different drugs by the Food and Drug Administration (FDA) for the treatment of SCD, particularly to reduce VOC and/or have an impact on the pathobiology of SCD. In this review, we outline the challenges and need for validation of side-effects of opioids and provide an update on the development of mechanism-based translational therapies, specifically targeting pain in SCD.