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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.