Circulating immune cells must exit blood vessels near specific target sites of injury, inflammation or tissue repair. The vessel wall at these sites displays specific combinations of traffic signals which operate in sequence to recruit only specific circulating subsets with proper receptors to these signals. As these processes take place under shear stress, these traffic molecules have evolved to operate under specialized kinetic and mechanical contexts. Using special flow chambers which simulate blood flow and intravital microscopy in genetically manipulated mice, we dissect how both endothelial and perivascular trafficking molecules promote context- and tissue- selective immune cell exit through distinct blood vessels. We also study how chemotactic and antigenic signals promote the stoppage of lymphocytes on dendritic cells and macrophages. This information is key for the development of novel therapeutic tools for inflammatory disorders, such as autoimmune diseases, atherosclerosis and organ rejection.