Sickle cell disease is an umbrella term for a group of hemoglobinopathies characterized by the presence of 2 β-globin gene mutations or deletions, at least 1 of which is the point mutation that leads to the production of hemoglobin S. Sickle cell disease is associated with hemolytic anemia, significant chronic end-organ damage, and early death. In high-income countries, at least 95% of children with the disease survive into adulthood, resulting in a growing population of affected adults with significant comorbidities, complex medical issues, and not enough specialists to provide care. Hydroxyurea is the primary therapy, and recent advances in understanding disease pathophysiology have led to new therapies; progress in bone marrow transplant and gene editing has resulted in cure in some patients. The purpose of this review is to provide an overview of the diagnosis, common acute and chronic clinical manifestations, and best practices for management of sickle cell disease.