Glioma, especially high-grade glioblastoma multiforme (GBM), is the most common and aggressive type of brain tumor, accounting for about half of all the primary brain tumors. Despite continued advances in surgery, chemotherapy, and radiotherapy, the clinical outcomes remain dismal. The 2-year survival rate of GBM is less than 30%. Better understanding of GBM biology is needed to develop novel therapies. Recent studies have demonstrated the existence of a small subpopulation of cells with stemlike features called cancer stem cells (CSCs). These GBM CSCs are self renewable and highly tumorigenic. They not only are chemo-radio resistant but also often contain multidrug resistance genes and drug transporter genes. These characteristics enable GBM CSCs to survive standard cytotoxic therapies. Among GBM CSCs, CD133(+) cells are a well-defined population and are prospectively isolated by their cell-surface marker. Increasing data show that the presence of CD133(+) CSCs highly correlates with patient survival, making these cells an ideal immunotherapy target population. The authors have reviewed recent studies related with GBM CSCs (particularly CD133(+) CSCs) and the novel therapeutic strategies targeting these cells.