Interactions of leukocytes with endothelial cells are early events in acute and chronic inflammation, immune surveillance of tissues, and wound defense and repair. In contrast with their requisite roles in host defense, dysregulated leukocyte–endothelial interactions mediate inflammatory tissue injury, thrombosis, and other pathologic sequelae. Recent observations also identify dysregulated leukocyte–endothelial interactions in neoplasia and sickle cell vasculopathy. Leukocyte interactions with inflamed endothelial cells are mediated by selectins, signaling molecules that include lipids and chemokines, integrins and their ligands, and junctional molecules. They provide multiple checkpoints for regulation in physiologic inflammation and hemostasis and for dysregulation in pathologic syndromes. Neutrophil–endothelial encounters illustrate a multistep paradigm for inflammatory cell–cell interactions and provide the basis for multiple variations on the central themes.