Sickle cell disease (SCD) is caused by a single-point mutation in the beta globin gene which creates abnormal, sickle hemoglobin, which polymerizes within the red blood cell (RBC) upon deoxygenation, creating poorly deformable cells. These RBCs not only cause blockages within the microvasculature leading to vaso-occlusion and end-organ damage, but they also exhibit procoagulant, proadhesive, and inflammatory properties. Furthermore, sickle RBCs cause endothelial cell activation and dysfunction via hemolysis and activation of platelets and inflammatory cytokines. Mouse models of SCD have been used to study endothelial dysfunction and vasculopathy; however, they are not without their limitations. In vitro microfluidic models to study SCD and sickle RBC–endothelial cell interactions can therefore provide a desirable alternative to the sickle mouse model. Here, we aim to discuss current bioengineering approaches being leveraged for the investigation of SCD vasculopathy.