A great deal of progress has been made recently in understanding the molecules and mechanisms that regulate transendothelial migration of leukocytes, or diapedesis, a critical step in the inflammatory response. This review focuses mainly on the active role of the endothelial cell in this process as it occurs at endothelial cell borders. It discusses some of the many molecules that have been reported to play a role in transendothelial migration and asks why so many molecules seem to be involved. The concept is emerging that diapedesis itself can be dissected into sequential steps controlled by specific molecule(s) at the endothelial cell border. Several mechanisms have been shown to play a critical role in transendothelial migration including signals derived from clustering of apically disposed intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, disruption or loosening of adherens junctions, and targeted recycling of platelet/endothelial cell adhesion molecule and other molecules from the recently described lateral border recycling compartment. A hypothesis that integrates the various known mechanisms is proposed.