Sickle cell disease (SCD) is a genetic blood disorder caused by abnormal hemoglobin that damages and deforms red blood cells (RBCs). The abnormal red cells break down, causing anemia, and obstruct blood vessels, leading to recurrent episodes of severe pain and multiorgan ischemic damage. SCD affects millions of people throughout the world and is particularly common among people whose ancestors come from sub-Saharan Africa. Sickle cell trait (SCT) is an inherited condition in which both normal hemoglobin and sickle hemoglobin are produced in the RBCs. SCT is not a type of sickle cell disease. People with SCT are generally healthy. In SCD, clinical severity varies, ranging from mild and sometimes asymptomatic states to severe symptoms requiring hospitalization. Symptomatic treatments exist, but there is no cure for SCD. Although there has been extensive clinical and basic science research in SCD, many public health issues, such as blood safety surveillance, compliance with immunizations, follow-up of newborns with positive screening tests, stroke prevention, pregnancy complications, pain prevention, quality of life, and thrombosis, in people with SCT remain unaddressed. Currently, efforts are under way to strengthen SCD-related activities within the Centers for Disease Control and Prevention (CDC). To date, several activities are being or have been conducted by centers within CDC, including quality assurance of newborn screening tests for SCD, morbidity and mortality studies, genetic studies, and studies focusing on the protective effects of SCT for malaria. This paper discusses the public health implications of SCD, summarizes SCD-related activities within CDC, and points to future directions that the agency can take to begin to address some of these issues.