Extracellular matrix (ECM) provides a physical scaffold for cells but also provides specific molecular and spatial information that influences cell proliferation, differentiation and apoptosis. This review addresses the multiple roles of ECM in inflammatory responses, in particular in leukocyte extravasation at sites of inflammation, and the potential of exploiting such cell-ECM interactions to interfere with defined steps in the inflammatory process. In the course of an inflammation leukocytes not only have to penetrate the vascular endothelial cell monolayer, but also the underlying endothelial cell basement membrane and invade the interstitial matrix of the stroma to reach the site of inflammation. The endothelial cell basement membrane may directly influence leukocyte recruitment to the inflammed tissue by providing differential signals resulting from its spatial and molecular composition, or indirectly by its potential to bind and present cytokines or chemotactic factors. Proteases (in particular matrix metalloproteinases (MMP)) released at sites of inflammation selectively process ECM and cell surface molecules, which may result in the release of bioactive fragments that may function as chemoattractants for different leukocytes subsets or modulate the activity/ function of resident mesenchymal and immune cells. In addition, MMPs have been shown to process chemokines modulating their chemoattractant properties. To be able to mimic or inhibit some of the ECM functions or proteolytic events that occur during inflammation, through the use of specific protein fragments, would provide a means by which the inflammatory process could be manipulated, an area however that remains largely unexplored.