Glioblastoma multiforme (GBM) is the most aggressive and common brain tumor, with an annual incidence of 3.19 per 100,000 people. Chemoresistance is a major issue in the treatment of GBM with therapeutics like temozolomide (TMZ), especially because of the challenges in making chemotherapeutics that can overcome the blood–brain barrier. Cancer stem cells, mechanisms of protein folding, drug pumps, and the tumor microenvironment have been noted as contributing to chemoresistance in GBM, but its precise molecular mechanisms remain unknown. Differential gene expression data from GSE140441 and GSE98126 was extracted from GEO2R, and we investigated the genes differentially expressed at the p<0.05 level between a control group of non-resistant subtypes and an experimental group of GBM cells cultured in TMZ to determine which could confer chemoresistance. The differentially expressed genes were identified and compiled using the dplyr package in R. These genes were submitted for DAVID functional annotation clustering. Clusters were analyzed for their significance at p<.05. From the differential expression studies, 1,980 genes were identified and used to conduct DAVID functional annotation clustering. From these genes, 101 functional annotation clusters were identified. Notably, many clusters responsible for mRNA regulation, as well as the clusters regulating conjugation of ubiquitin-like protein (p=1.2E-17) and cadherin binding (p=1.9E-5) clusters, were significantly differentially expressed in chemoresistant GBM. Targeting pathways related to conjugation of ubiquitin-like protein and cadherin binding, as well as other mechanisms of protein breakdown, might further our understanding of the mechanism of chemoresistance in GBM while also improving the clinical utility of treatments. Certain FDA-approved drugs that target both the ubiquitin-like protein degradation pathway and DNA synthesis, including mitoxantrone, 6-mercaptopurine, and 6-thioguanine, should be explored for possible use as drugs to sensitize chemoresistant GBM. Inhibition of the cadherin binding pathway may also be a novel method of overcoming adaptive mechanisms in GBM.