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Sickle cell disease (SCD), the commonest monogenetic disorder worldwide, represents a major public health burden because of its significant morbidity and mortality. Advances in molecular and cellular biology have resulted in an accumulation of knowledge on sickle cell pathophysiology and broadened our understanding of the complexity of this molecular disease with heterogeneous manifestations. Natural history studies and clinical trials have provided incremental data on clinical features, complications, and predictors of severity in SCD and, above all, have laid important recommendations for prevention and treatment of complications. Disease modifying therapies that have significantly improved survival of SCD patients have been identified over recent years. Despite increasingly successful therapies and better overall survival, patients continue to die especially with increasing age and health providers caring for SCD patients face major challenges. This article will highlight modern management of SCD and its impact on the lives of affected patients.