© 2001 Macmillan Magazines Ltd REVIEWS Cell interactions with the extracellular matrix (ECM) and with neighbouring cells trigger numerous responses that have essential roles in the regulation of their behav- iour and fate 1,2 . ECM adhesion and assembly affect cells in many ways. As the ECM provides the physical microenvironment in which cells live, it provides a sub- strate for cell anchorage and serves as a tissue scaffold, guides cell migration during embryonic development and wound repair, and has other key roles in tissue morphogenesis. However, beyond these obvious scaf- folding functions, the ECM is also responsible for trans- mitting environmental signals to cells, which affect essentially all aspects of a cell’s life, including its prolifer- ation, differentiation and death. So, selection of the appropriate matrix for experiments using cultured cells is crucial, as it can profoundly affect the cellular response. As will be discussed below, not only is the molecular composition of the ECM important, but also its topography and mechanical properties 3–6 . These fea- tures of the ECM are determined both by the cells that produce it and by the cells that grow on or inside the matrix. So, the life of a cell seems to involve intense and complex crosstalk with the matrix. In this review, we focus on the molecular events that occur at both faces of the cell membrane in cell–matrix adhesions. We describe briefly the molecular organiza- tion and complexity of the membrane–cytoskeleton interface in this region, as well as external interactions with the ECM.We show how cells actively shape the matrix around them, and that the entire process is con- trolled both locally and globally by specific regulatory pathways, with a mechanosensory system and molecu- lar switches acting as pivotal elements.We also consider several puzzles in rapidly developing areas that provide intriguing opportunities for new advances. Cell–matrix adhesions Adhesions with the ECM are formed by essentially all types of adherent cell, but their morphology, size and subcellular distribution can be quite heterogeneous. Many of these adhesions, nevertheless, share two com- mon features — they are mediated by INTEGRINS, and they interact with the actin cytoskeleton at the cell inte- rior. The extracellular ligands that anchor these adhe- sions include fibronectin, vitronectin and various colla- gens. The best-characterized adhesions are the ‘classical’ focal adhesions (also termed focal contacts), and vari- ants include fibrillar adhesions, focal complexes and podosomes (FIG. 1 and TABLE 1). Focal adhesions are flat, elongated structures that are several square microns in area, and are often located near the periphery of cells 7–10 . Focal adhesions mediate TRANSMEMBRANE EXTRACELLULAR MATRIX– CYTOSKELETON CROSSTALK Benjamin Geiger*, Alexander Bershadsky*, Roumen Pankov ‡ and Kenneth M. Yamada ‡ Integrin-mediated cell adhesions provide dynamic, bidirectional links between the extracellular matrix and the cytoskeleton. Besides having central roles in cell migration and morphogenesis, focal adhesions and related structures convey information across the cell membrane, to regulate extracellular-matrix assembly, cell proliferation, differentiation, and death. This review describes integrin functions, mechanosensors, molecular switches and signal-transduction pathways activated and integrated by adhesion, with a unifying theme being the importance of local physical forces. NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 2 | NOVEMBER 2001 | 793 *Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel. ‡ Craniofacial Developmental Biology and Regeneration Branch, National Institute of Craniofacial and Dental Research, National Institutes of Health, Bethesda, MD 20892, USA Correspondence to B.G. e-mail: benny.geiger@weizmann.ac.il INTEGRINS A group of heterodimeric transmembrane adhesion receptors for extracellular- matrix proteins such as fibronectin and vitronectin.