The migration of leukocytes from the vascular lumen to the extravascular tissue is one of the most dramatic cellular responses observed at sites of inflammation and is a critical event in both innate and adaptive immunity. To achieve this, finely co-ordinated mechanisms must exist by which leukocytes are able to penetrate the vascular wall and migrate into sites of injury or infection without causing gross damage to the vessels from which they emigrate. Despite the tremendous interest in this response and its fundamental role in inflammation, details of the mechanisms by which leukocytes penetrate the vascular wall remain largely unknown. The slow progress in understanding this response is attributable to the complex nature of the vessel wall and the difficulties associated with modelling it in vitro. Specifically, venular walls have two distinct cellular components, endothelial cells (ECs) and pericytes, both of which appear to contribute to the generation of the matrix component of the vessel wall, its basement membrane. Through formation of complex molecular organisations between adjacent cells, ECs form a confluent layer within the vessel wall and provide the first barrier for emigrating leukocytes. It is generally considered that migrating leukocytes penetrate this barrier by seeking and moving through these junctions and there is now a growing understanding of the mechanisms that mediate this process. Specifically, in addition to PECAM-1, the first EC junctional molecule shown to be involved in leukocyte transendothelial cell migration, there is now substantial in vitro and some in vivo evidence for the involvement of several other molecules including ICAM-2, members of the JAM family, CD99 & ESAM. Despite this growing knowledge, details of the precise involvement of such molecules is however currently unknown and is likely to be complex as the available data implies differential roles of endothelial cell junctional molecules in mediating different stages of leukocyte transmigration, transmigration of different leukocyte sub-types as well as mediating leukocytes transmigration in different vascular beds and in response to different inflammatory stimuli. In addition to migration through EC junctions (paracellular route), there is now a renewed interest in the significance and mechanisms by which leukocytes migrate through the body of the endothelium (transcellular route) though the mechanisms by which this occurs in vivo are not known. Furthermore, there are no indications of the inflammatory conditions that drive leukocytes to migrate via the transcellular route as opposed to the paracellular route. The perivascular basement membrane (BM) provides a distinct and effective barrier to leukocytes and macromolecules, a barrier that has to be breached at sites of inflammation. Recent findings from our group have led to the identification of neutrophil permissive sites within the BM of mouse cremasteric venules. In these regions the expression of certain BM constituents (eg laminin 10 & collagen IV) were found to be lower than the average level (termed low-expression or LE sites) and the regions appeared to be preferential sites of neutrophil emigration. As these regions were directly co-localised with gaps between pericytes, neutrophil transmigration occurred specifically at sites of least resistance, ie gaps between adjacent pericytes and regions of low protein deposition within the BM. Of interest, neutrophil migration through LE regions resulted in a transient enlargement of these sites, a response that appeared to involve neutrophil elastase. Collectively, leukocyte transmigration through venular walls involves complex mechanisms that guide leukocytes through the EC barrier and is also associated with elaborate remodelling of the vascular BM. These multiple barriers also appear to facilitate the transmigration process by eliciting distinct signals to transmigrating cells thus inducing an efficient and well-coordinated transmigration response.