An active area of research in the field of regenerative medicine involves the development of bioactive matrices that can promote cellular interactions and elicit desirable regenerative behavior in vivo. This is particularly important in the context of ischemic stroke where a focal lesion forms preventing the regrowth of brain tissue. Protein-based molecules have been used as building blocks to create supramolecular structures that emulate the properties of the native healthy extracellular matrix (ECM) within the central nervous system (CNS). In this review, we briefly describe the relevant biological aspect of stroke and the techniques found in molecular biology and biochemical synthesis methodologies used in the design and synthesis of novel biomaterials. Within these biomaterials, researchers are able to incorporate a number of different domains that trigger assembly or promote cell growth and survival and direct transplanted or endogenous stem cell behavior within the 3D hydrogel scaffolds. Such domains may also yield stimuli-responsive biomaterial scaffolds where the structure of the hydrogel undergoes a change in response to the local environment. These highly modular proteinaceous materials allow incorporation of diverse biofunctional motifs and structural elements comparable to those found in native ECM. We explore CNS relevant biomaterials that promote cell survival and host tissue integration and discuss their applications to stem cell therapy in the treatment of stroke.