Sickle cell disease (SCD) is a group of complex genetic disorders with multisystem manifestations. This statement provides pediatricians in primary care and subspecialty practice with an overview of the genetics, diagnosis, clinical manifestations, and treatment of SCD. Specialized comprehensive medical care decreases morbidity and mortality during childhood. The provision of comprehensive care is a time-intensive endeavor that includes ongoing patient and family education, periodic comprehensive evaluations and other disease-specific health maintenance services, psychosocial care, and genetic counseling. Timely and appropriate treatment of acute illness is critical, because life-threatening complications develop rapidly. It is essential that every child with SCD receive comprehensive care that is coordinated through a medical home with appropriate expertise.