Blood cell interactions with the vessel wall were first documented almost 170 years ago. Modern advances have revealed that leukocyte and platelet interactions with the endothelium are at the nexus of complex, dynamic cellular and molecular networks that, when dysregulated, may lead to pathological inflammation and thrombosis, which are major sources of morbidity and mortality in the Western world. In this review, we relate the history of blood cell interactions with the vasculature, discuss recent progress, and raise some unresolved questions awaiting the field.