Research regarding the interactions between the endothelium and immune cells has undergone a significant expansion during the past decade. Major shifts of emphasis have been the norm, from the production of a detail catalog of the cell surface receptors and counter-receptors acting at the interface between the vascular endothelium and circulating cells to a more mechanistic account of leukocyte / endothelium interactions. The past five years has seen new, groundbreaking developments in the field, with exiting studies aimed at understanding the functional consequences of the direct contact of endothelial cells and leukocytes. Based on early work to be discussed below, new data on local chemokine production and cell-to-cell contacts, attempt to clarify the physiopathological significance of these events. The exceptional anatomical arrangement of endothelial cells insures a permanent contact of the endothelium with leukocytes, an event likely to result in cellular signals originating from direct cell contact or through the action of soluble factors produced by endothelial cells or immune cells. As we will discuss, current evidence supports the idea that endothelial cells present at vascular endothelium as well as at specialized high endothelial venules, play not only a critical role in the homing and recruitment of immune cells but that it can also influence the outcome of the immune response. Additionally, new evidence clearly corroborates the idea that B and T lymphocytes as well as NK cells can modulate endothelial cell function.