Endothelial paracellular junctions are important structures for the regulation of vascular permeability, junctional organisation being systematically related to the functional properties of the endothelium. Electron microscopic studies, immunocytochemistry, and single-passage permeability measurements have established that the placental microvessels resemble the fairly tight continuous microvessels of skeletal muscle both in structure and permeability. The endothelial paracellular clefts of these microvessels contain two distinct junctional entities which may influence permeability: the tight junction and the adherens junction. These clefts impose a substantial restriction to molecules above RMM 1000 Da and large haemproteins cannot cross the clefts. The 18 nm-wide zones of the clefts possess the transmembrane adhesion molecules PECAM-1 and VE-cadherin, which have been implicated in junctional assembly and permeability. Inflammatory mediators such as histamine and tumour necrosis factor cause a redistribution of these adhesion molecules to non-junctional regions, and histamine (100 microM) causes a rapid and sustained rise in extraction of radio-labeled tracers. Electron microscopy has also revealed possible first indications of tight junctional disassembly. Both the endothelia of larger placental vessels and isolated placental microvascular endothelial cells express cadherins and PECAM-1 and contain an extensive F-actin cytoskeleton, which is implicated in changes of cell shape and junctional assembly/disassembly. Thus, the human placental endothelium, using perfusion techniques and in vitro experiments, offers a valuable model for vascular permeability studies.