Cellular interactions with the extracellular matrix (ECM) are of fundamental importance in many normal and pathological biological processes, including development, cancer, and tissue homeostasis, healing and regeneration. Over the past few years, the mechanisms by which cells respond to the mechanical characteristics of the ECM have come under increased scrutiny from many research groups. Such research often involves placing cells on materials with tuneable stiffnesses, including synthetic polymers and natural proteins, or culturing cells on bendable micropost arrays. These techniques are often aimed at defining empirically the stiffnesses that cells experience in their interactions with the ECM, and measuring phenotypically how cells and tissues respond. In this review, we will summarise the evolution of materials for investigating cell and tissue mechanobiology. We then will discuss how material properties such as elastic modulus may be interpreted, particularly with regard to analytic measurements as an approximation of how cells themselves sense elastic modulus. Finally we will discuss how factors such as interfacial chemistry, ligand spacing, substrate thickness, elasticity and viscoelasticity affect mechanosensing in cells.