The migration of leukocytes from the vascular lumen to sites of infection and/or injury in the extravascular tissue involves a series of sequential and coordinated molecular and cellular events with the resultant primary response being that of reduced leukocyte velocity within the blood stream, followed by leukocyte firm adhesion to endothelial cells lining the vessel wall and eventually migration through the vessel wall. Despite the growing knowledge of the mechanisms that mediate initial interaction of leukocytes with the endothelium, very little is known about the mechanisms that mediate and regulate leukocyte migration through the venular wall, the endothelium and its associated perivascular basement membrane. This review, whilst giving a brief outline of the stepwise cascade of molecular interactions involved in this process and the methods employed to investigate leukocyte migration in vivo, focuses primarily on mechanisms of leukocyte transmigration, the final step in the process of leukocyte emigration. Furthermore, special emphasis is placed on discussing the process and the mechanisms involved in leukocyte migration through the basement membrane, a structure that presents significant impedance to transmigrating leukocytes but is seldom investigated in the context of leukocyte transmigration in vivo. The review also discusses the growing evidence supporting the concept that leukocyte transmigration is not only a response that describes the passage of leukocytes through the venular wall, but also acts as a means of regulating leukocyte responsiveness beyond the vessel wall, i.e. within the extravascular tissue.