Over the past decades there has been a significant improvement in the care of patients with sickle cell disease (SCD) in high-income countries. However, more needs to be learned about the complex pathophysiology and the factors that contribute to the development of end organ damage from the disease. While antibiotic prophylaxis and appropriate treatment of infections have resulted in a significant reduction of early mortality, management of the painful episodes and prevention of organ damage remain a challenge. Hydroxyurea is the only medication approved as disease-modifying therapy, and bone marrow transplant as curative treatment is not available to most patients. In low-income countries with the highest disease burden, early mortality is high due to limited resources for systematic screening, early diagnosis, and disease management. In order to improve outcomes in patients with SCD in high-income countries, better and widespread implementation of known disease-modifying therapies and the development of newer therapies targeting key pathophysiologic pathways are required. In low-income countries with high disease burden, innovative approaches to develop low-cost diagnostic devices and treatments that can be implemented to scale are needed to combat early mortality from the disease. Sustainable solutions in low-resource settings require evidence-based affordable interventions that can be integrated into primary and secondary healthcare systems.