Ischemic stroke poses a massive burden of disease and continues to be a leading cause of morbidity and mortality throughout the world. However, beyond thrombolysis/mechanical thrombectomy we possess few effective therapies that are able to modulate the pathogenesis of evolving ischemic brain injury. The paucity of therapeutic options stands in stark contrast to the intensity of research efforts/number of clinical trials that have been performed to date. Further, there are, as of yet, no effective treatments (neurorehabilitation notwithstanding) that improve functional recovery in post-ischemic patients (i.e. regenerative therapies). The restricted success of such a massive research investment demands a re-evaluation of the pathobiology of ischemic brain injury and a subsequent adjustment of therapeutic approaches. While reductionist methods (e.g. the targeting of single proteins/pathways) have done much to enhance our understanding of ischemic brain injury, accumulating evidence has come to suggest that beyond the restoration of perfusion (i.e. the proximate driver of the pertinent pathobiology), it will likely not be possible to identify a single dominant therapeutic target. Therefore, a focus on i) plurifunctional molecular pathways and ii) plurifunctional therapeutic modalities capable of influencing brain ischemia are urgently warranted. A candidate pathway that has been demonstrated to be involved in the multifaceted ischemic response is the post-translational modification (PTM) of proteins by the Small Ubiquitin-like MOdifier (SUMO) protein(s) via a process dubbed SUMOylation. The upregulation of this pathway has been shown to be capable of maintaining homeostasis in natural models (e.g. hibernation) and in preclinical models of brain ischemia. As such, identifying small molecules that upregulate the plurifunctional SUMOylation process may have the potential to protect vulnerable (e.g. penumbral) tissue after an ischemic insult. Unfortunately, reliable/clinically feasible methods of achieving such a goal are currently lacking. In an effort to protect and/or repair the ischemic brain, a multitiered therapeutic approach to brain ischemia may be centred on the use of neural stem cells (NSCs). NSCs exert beneficial effects not only via the structural replacement of dysfunctional and/or damaged cells, but also via immunomodulatory and neurotrophic actions. Unfortunately, the successful translation of such promising cell-based approaches remains elusive, in part due to the fact that NSCs often die in the hostile ischemic/post-ischemic microenvironment. Therefore, the aims of this thesis were to i) identify drugs which upregulate SUMOylation in the ischemic brain/cells and ii) generate and characterize somatic NSCs in which SUMOylation is upregulated for transplantation in ischemic mouse models in an effort to influence their survival and engraftment. If either of these approaches succeed, they may find utility not only in the realm of stroke therapy, but could also extend to a wide variety of other degenerative/inflammatory neurological disorders that share components of stroke pathobiology (e.g. Alzheimer’s, multiple sclerosis, spinal cord injury etc.).