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. For biologically derived materials, methods are being sought to gain molecular-level control over biological characteristics and biomechanics. For synthetic, biomimetic materials, chemical schemes are being developed to enable in situ cross-linking and protease-dependent degradation and release of incorporated growth factors. These materials will open new doors to biosurgical therapeutics in tissue engineering and regenerative medicine.