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Cover   Intimate connections between the actin-based cytoskeleton and the fibronectin-rich extracellular matrix have been studied intensively for the past 20 years and continue to be the focus of much current research. Work of Irwin Singer (Cell 16, 675-685, 1979) using electron microscopy demonstrated these connections in particularly graphic fashion, extending earlier immunofluorescence evidence for a close relationship between the cytoskeleton and the matrix. Images such as the one shown played an important role in motivating research into the molecular nature of the transmembrane connection since it seemed clear that neither the matrix fibrils nor the microfilaments themselves were integral membrane proteins. Several years later the transmembrane proteins were identified as integrins (Hynes, Cell 48, 549-554, 1987). Integrins bind both to extracellular matrix molecules, acting as cell adhesion receptors, and also to cytoskeletal proteins forming a crucial link between the two structures at sites of close apposition known variously as focal contacts, focal adhesions or extracellular matrix contacts or, in Singer's paper, as "the fibronexus." It has now become clear that these integrin-mediated connections serve as more than mechanical links, being the sites of elaborate signaling complexes (Clark and Brugge, Science 268, 233-239, 1995; Schwartz et al. Annu. Rev. Cell Dev. Biol. 11, 549-599, 1995). These complexes transduce signals both into the cell, affecting a wide variety of intracellular events, including cytoskeletal organization, cellular proliferation and survival and gene expression, and out of the cell, regulating the ability of the integrins to bind to their extracellular ligands. Indeed, it is now clear that extracellular matrix signaling through integrins is as important for cell behavior as the signaling mediated by soluble hormones and growth factors. This signaling function occurs at the sites of mechanical connections illustrated so nicely in the work of Singer. Arrows point to matrix on left and to microfilaments on right.Richard O. Hynes