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Sickle cell disease is characterized by recurrent, painful episodes and organ damage resulting from microvascular occlusion. Seminal studies performed 20 years ago revealed increased adherence of sickle erythrocytes to vascular endothelial cells. Subsequent work showed that these interactions were mediated by multiple adhesion pathways, but the relevance of these interactions has not been evaluated in vivo. Clinical data suggest that leukocytes may play a role, because leukocytosis correlates with clinical severity and early death, and administration of myeloid growth factors to patients can precipitate sickle cell crises. In addition, recent experimental data using intravital microscopy indicate that sickle erythrocytes can interact with adherent leukocytes in inflamed postcapillary and collecting venules. A novel multistep model for sickle cell vaso-occlusion is proposed in which endothelial activation is induced by sickle cells or secondary inflammatory stimuli and leads to the recruitment of adherent leukocytes. The resulting adherent leukocytes interact with circulating sickle erythrocytes, and this interaction impedes microvascular blood flow. Finally, irregularly shaped sickle cells become nonspecifically trapped, resulting in vaso-occlusion. The molecular mechanisms and requirements for the heterotypic interactions between erythrocytes and leukocytes are currently unknown and may involve further activation of adherent leukocytes or circulating erythrocytes. This model offers exciting new opportunities for therapeutic intervention and suggests a critical participation of adherent leukocytes in sickle cell vaso-occlusion.