Biomaterial matrices are being developed that mimic the key characteristics of the extracellular matrix, including presenting adhesion sites and displaying growth factors in the context of a viscoelastic hydrogel. This review focuses on two classes of materials: those that are derived from naturally occurring molecules and those that recapitulate key motifs of biomolecules within biologically active synthetic materials. We also discussed some of the most significant biological features of the ECM, and several engineering methods currently being implemented to design and tune synthetic scaffolds to mimic these features. Understanding the cell-protein-material interaction is fundamental for developing more powerful tools in tissue engineering and regenerative medicine strategies. The design of model substrates including the presence of well-defined properties (chemistry, topography, stiffness) and even the gradient of these properties in three dimensional environments must lead in the near future to learn more about the specific roles of protein adsorption and the very dynamic process related to the cell fate of synthetic substrates: cell adhesion, matrix reorganisation, deposition and degradation at the cell-material interface. These materials will open new doors to biosurgical therapeutics in tissue engineering and regenerative medicine.