Cancer stem cells (CSCs) in glioblastoma (GBM) are self-renewing, tumorigenic cells that contribute to tumor initiation and therapeutic resistance. GBM, the most prevalent and lethal primary brain tumor, contains CSCs that mimic normal stem cells in their developmental programs, enabling tumor growth and progression. CSCs function within an ecological system, interacting with their microenvironment and receiving signals from niches. Understanding CSC mechanisms has led to the development of targeted therapies for GBM and other brain cancers. However, CSCs are not self-autonomous and require interaction with their environment for survival and function. CSCs are defined by their ability to self-renew, generate differentiated progeny, and initiate tumors upon transplantation. They are distinct from normal stem cells, though some features overlap. CSCs are not uniformly identifiable by markers like CD133, which can be misleading due to its context-dependent expression. Other markers, such as integrin α6, CD15, and CD44, have been proposed but are not universally informative. Neurosphere culture and flow cytometry-based methods for isolating CSCs have limitations, as they may not fully represent the heterogeneity of the tumor. CSC regulation involves intrinsic factors like genetics, epigenetics, and metabolism, as well as extrinsic factors such as the microenvironment, niche factors, and the immune system. Genetic mutations, including IDH1 and TERT promoter mutations, are common in GBM and influence CSC behavior. Epigenetic modifications, such as those involving histone acetylation and methylation, also play a role in maintaining the CSC state. Metabolic pathways, including aerobic glycolysis and the pentose phosphate shunt, are crucial for CSC survival under hypoxic and acidic conditions. Extrinsic factors, such as Notch, Wnt, and Hedgehog signaling pathways, are critical for CSC maintenance and function. These pathways are co-opted by CSCs to maintain an undifferentiated state, enhancing their survival and proliferation. The immune system also interacts with CSCs, with CSCs modulating immune responses and potentially being targeted for immunotherapy. Anti-angiogenic therapies, such as bevacizumab, have shown limited success in GBM due to the tumor's ability to adapt and resist treatment. Therapeutic resistance in GBM is partly due to the presence of CSCs, which can repopulate tumors after treatment. Targeting CSCs requires understanding their molecular mechanisms, including DNA repair pathways, Notch, NF-κB, and EZH2. Therapeutic strategies, such as PARP inhibitors and immunotherapy, are being explored to overcome resistance. Mathematical modeling is also being used to understand CSC dynamics and predict therapeutic responses. Future research aims to clarify the heterogeneity of CSCs, their interactions with the microenvironment, and the role of developmental signaling pathways in their function. Integrating mathematical models with biological data willCancer stem cells (CSCs) in glioblastoma (GBM) are self-renewing, tumorigenic cells that contribute to tumor initiation and therapeutic resistance. GBM, the most prevalent and lethal primary brain tumor, contains CSCs that mimic normal stem cells in their developmental programs, enabling tumor growth and progression. CSCs function within an ecological system, interacting with their microenvironment and receiving signals from niches. Understanding CSC mechanisms has led to the development of targeted therapies for GBM and other brain cancers. However, CSCs are not self-autonomous and require interaction with their environment for survival and function. CSCs are defined by their ability to self-renew, generate differentiated progeny, and initiate tumors upon transplantation. They are distinct from normal stem cells, though some features overlap. CSCs are not uniformly identifiable by markers like CD133, which can be misleading due to its context-dependent expression. Other markers, such as integrin α6, CD15, and CD44, have been proposed but are not universally informative. Neurosphere culture and flow cytometry-based methods for isolating CSCs have limitations, as they may not fully represent the heterogeneity of the tumor. CSC regulation involves intrinsic factors like genetics, epigenetics, and metabolism, as well as extrinsic factors such as the microenvironment, niche factors, and the immune system. Genetic mutations, including IDH1 and TERT promoter mutations, are common in GBM and influence CSC behavior. Epigenetic modifications, such as those involving histone acetylation and methylation, also play a role in maintaining the CSC state. Metabolic pathways, including aerobic glycolysis and the pentose phosphate shunt, are crucial for CSC survival under hypoxic and acidic conditions. Extrinsic factors, such as Notch, Wnt, and Hedgehog signaling pathways, are critical for CSC maintenance and function. These pathways are co-opted by CSCs to maintain an undifferentiated state, enhancing their survival and proliferation. The immune system also interacts with CSCs, with CSCs modulating immune responses and potentially being targeted for immunotherapy. Anti-angiogenic therapies, such as bevacizumab, have shown limited success in GBM due to the tumor's ability to adapt and resist treatment. Therapeutic resistance in GBM is partly due to the presence of CSCs, which can repopulate tumors after treatment. Targeting CSCs requires understanding their molecular mechanisms, including DNA repair pathways, Notch, NF-κB, and EZH2. Therapeutic strategies, such as PARP inhibitors and immunotherapy, are being explored to overcome resistance. Mathematical modeling is also being used to understand CSC dynamics and predict therapeutic responses. Future research aims to clarify the heterogeneity of CSCs, their interactions with the microenvironment, and the role of developmental signaling pathways in their function. Integrating mathematical models with biological data will