Cells in our tissues are exposed to complex arrays of biochemical and biophysical cues from their protein- and sugar-rich extracellular matrix (ECM). In concert with cell- intrinsic regulatory cascades, these temporally and spatially coordinated signals instruct cells to acquire specific fates, controlling, for example, cell division, differentiation, migration or apoptosis. Conversely, cells are constantly secreting signals that can trigger structural and biochemical microenvironmental changes, as is most evident during proteolytic remodeling of the ECM. The resulting reciprocal and dynamic cell-matrix interaction is crucial for tissue development, maintenance and regeneration and, if gone awry, it can be involved in disease progression such as tumor metastasis. Recent efforts in the development of synthetic biomaterials for tissue engineering aimed to mimic the cell-instructive and cell-responsive function of ECMs. This chapter focuses on the molecular design, function and application of such smart biomaterials as cell-responsive artificial ECMs that can for example actively participate in cascades of morphogenesis during tissue regeneration (see also other chapters in this book).