Sickle cell disease (SCD) is an inheritable hemoglobinopathy characterized by polymerization of hemoglobin S in red blood cells resulting in chronic hemolytic anemia, vaso-occlusive painful crisis, and multiorgan damage. In SCD, an increased reactive oxygen species (ROS) generation occurs both inside the red blood cells and inside the vascular lumen, which augment hemolysis and cellular adhesion. This review discusses the evolving body of literature on the role of ROS in the pathophysiology of SCD as well as some emerging therapeutic approaches to SCD with a focus on the reduction of ROS.