SCD is the quintessential chronic disease of childhood, manifesting signifcant clinical sequelae despite a defned molecular origin. Children and adults with SCD are anemic, make frequent emergency department visits, and are often hospitalized for pain and acute complications associated with progressive organ damage. Mortality for patients with SCD in high-income countries is shifting from infectious and cerebrovascular complications in childhood to progressive multisystem organ failure (MSOF) in adulthood . An expanding population of adults with SCD, the happy result of decades of improved pediatric care, is facing the multifaceted consequences of decades of chronic and cumulative vascular damage. However, there is new hope for treating people with SCD. Hydroxyurea (HU) modulates many complications of SCD, and hematopoietic stem cell transplant (HSCT) is curative. Gene therapies and genome editing (of the gene itself or disease-modifying genes) are transforming prospects for curative therapy in single-gene disorders like SCD . In this setting, clinicians, patients, and their families are increasingly challenged by the complicated therapeutic risk-beneft analyses for a disease that may be mild in children but can cause relentless morbidity and early mortality in adults . Figure 1.1 provides an overview of major milestones in SCD since its recognition as a pathobiologically distinct hemolytic anemia in the early decades of the last century.