Genomic analyses have become an important tool to identify new avenues for therapy. This is especially true for cancer types with extremely poor outcomes, since our lack of effective therapies offers no tangible clinical starting point to build upon. The highly malignant brain tumor glioblastoma (GBM) exemplifies such a refractory cancer, with only 15 month average patient survival. Analyses of several hundred GBM samples compiled by the TCGA (The Cancer Genome Atlas) have produced an extensive transcriptomic map, identified prevalent chromosomal alterations, and defined important driver mutations. Unfortunately, clinical trials based on these results have not yet delivered an improvement on outcome. It is, therefore, necessary to characterize other regulatory routes known for playing a role in tumor relapse and response to treatment. Alternative splicing affects more than 90% of the human coding genes and it is an important source for transcript variation and gene regulation. Mutations and alterations in splicing factors are highly prevalent in multiple cancers, demonstrating the potential for splicing to act as a tumor driver. As a result, numerous genes are expressed as cancer-specific splicing isoforms that are functionally distinct from the canonical isoforms found in normal tissue. These include genes that regulate cancer-critical pathways such as apoptosis, DNA repair, cell proliferation, and migration. Splicing defects can even induce genomic instability, a common characteristic of cancer, and a driver of tumor evolution. Importantly, components of the splicing machinery are targetable; multiple drugs can inhibit splicing factors or promote changes in splicing which could be exploited to begin improving clinical outcomes. Here, we review the current literature and present a case for exploring RNA processing as therapeutic route for the treatment of GBM.