The extracellular matrix (ECM) provides signalling cues that regulate cell behaviour and orchestrate functions of cells in tissue formation and homeostasis. The composition of the ECM, its three-dimensional organization and proteolytic remodelling are major determinants of the microenvironmental signalling context that controls cell shape, motility, growth, survival and differentiation. In recent years, the importance of ECM signalling has been underscored by the evidence that misregulation of cell-ECM interactions can contribute to many diseases, including developmental, immune, haemostasis, degenerative and malignant disorders. This review discusses recent insights into the regulatory functions of the ECM and their role in disease, focusing on cancer as a paradigm.