Neuro-diseases can affect broadly the central nervous system (CNS), such as degenerative diseases, or result from a localized trauma as Traumatic Brain Injury (TBI) or stroke. Once the homeostasis of the brain and/or its surroundings (e.g. glia, ECM) are compromised the treatment is a challenge, as the CNS possesses low endogenous capacity to self-repair, along with the specificity and complexity that need to be correctly restored, otherwise rends them useless. Biomaterials have been increasingly studied for CNS-related diseases, with special focus on natural-based hydrogels, due to their brain-like consistency and porosity, allowing molecule exchange. More interesting is the possibility to tune the biomaterials’ physicochemical properties to meet specified needs, and/or combined them with for example cells or genes, to further complement the therapy. Moreover, hydrogels can be injected in the liquid form and let to gelify in situ, avoiding invasive administrations. The combination of several components allows a more targeted and controlled delivery, and/or to tackle events occurring simultaneously in brain diseases (e.g. cell death and inflammation). The complexity of CNS-related pathologies will be reviewed as well as encouraging studies with biomaterials, cells and genes.