The vaso-occlusion model has evolved impressively over the past several decades from polymerization-based concepts to a complex, wide-ranging schema that involves multistep, heterogeneous, and interdependent interactions among sickle erythrocytes (SSRBCs), adherent leukocytes, endothelial cells, plasma proteins, and other factors. Endothelial activation, induced directly or indirectly by the proinflammatory behavior of SSRBCs, is the most likely initiating step toward vaso-occlusion. Given the complexity and dynamic relationships of the potential mechanisms leading to vaso-occlusion, further in vivo studies in relevant sickle cell animal models will most likely yield the greatest advances and promote the development of novel, more effective therapeutic strategies.