Sickle cell disease is a genetic red blood cell disorder, affecting millions of people globally. This Seminar provides a comprehensive update on the disease, emphasising its complex pathophysiology involving sickle haemoglobin polymerisation, vaso-occlusion, haemolysis, and inflammation that lead to acute, life-threatening complications and progressive organ damage. We review the spectrum of the most frequent acute manifestations—vaso-occlusive crises, acute chest syndrome, stroke, and infections—alongside chronic complications affecting virtually all organ systems. Recent advances include expanded implementation of hydroxyurea in low-resource settings and the optimisation of hydroxyurea protocols, refined transfusion therapy, improved haematopoietic stem cell transplantation outcomes with alternative donor strategies, and gene therapies now approved for clinical use. Additionally, new drugs are being evaluated in clinical trials globally. We examine successful implementation strategies in low-income and middle-income countries using point-of-care diagnostics and integrated care models. Controversies and challenges include the management of sickle haemoglobin-C and haemoglobin S/β⁺ variants, cerebrovascular complication prevention, hydroxyurea use in pregnancy, and the transition from paediatric to adult care.