Sickle cell disease (SCD) is an inherited hemoglobinopathy that leads to significant lifetime morbidity and early mortality. An enhanced understanding of the complex pathophysiology of the disease has elucidated novel therapeutic targets for which new therapies are in development. In order to increase the therapeutic landscape, it has been important to identify the blood vessel and more specifically the endothelium as the target organ in this complex disease. Through this lens, we present a review of new anti-adhesion therapies for SCD in development. The long-term promise of multimodal therapies for SCD is finally on the horizon.