Glioblastoma (GBM) poses a formidable challenge to patients for several reasons. Given its grim prognosis, understanding the various mechanisms GBM tumors utilize to resist therapy is essential to improve patient outcomes. Using PubMed, this focused review identifies and characterizes five critical elements of GBM tumors that contribute to their resistance to treatment: DNA repair enzymes, temozolomide (TMZ) and radiation mechanisms, anti-apoptosis mechanisms, GBM tumor heterogeneity and its effects on the cell cycle. This review explores various challenges associated with GBM tumors, such as their resistance against standard treatments such as TMZ and radiation therapy (RT). We explore the importance of epigenetic reprogramming, genetic mutations critical for cell proliferation and tumor suppression, and the role of mismatch repair (MMR) processes that influence RT and immune response interplay as contributors to GBM resistance. In addition, this review highlights vital DNA repair enzymes such as O6-methylguanine-DNA methyltransferase (MGMT) and Alkylpurine-DNA N-Glycosylase (APNG), which repair DNA damage introduced by alkylating agents such as TMZ. The involvement of the NuRD complex, particularly CHD4, in regulating access to DNA repair enzymes. Recent advancements in understanding the transcriptional regulation of MGMT through NF-κB activity are examined. Further, we explore novel approaches, including using anticancer neural stem cells and targeting hexokinase 2 (HK2) with antifungal drugs. Examining critical elements of the GBM cell cycle, such as the role of CDK's, cyclin(s) and proliferation markers such as ki67, can also give us a foundation for identifying possible target proteins and kinases for cancer drugs. While targeting DNA repair enzymes, proteins, and regulatory elements shows promise in enhancing GBM treatment efficacy, we acknowledge the challenges, including potential side effects and the risk of secondary cancers. Future research should focus on leveraging personalized medicine approaches and emerging biotechnologies, such as CRISPR gene editing, to develop targeted therapies that can overcome resistance mechanisms of GBM and improve patient outcomes.