Glioblastoma remains one of the deadliest forms of cancer. Infiltrating cancer cells in the surrounding brain prevent complete resection, and tumor cell resistance to chemoradiation results in the poor prognosis of the glioblastoma (GBM) patient. Much research has been devoted over the years to the pathogenesis and treatment of GBM. The tumor stem cell hypothesis, which was initially described in hematopoietic cell malignancies, may explain the resistance of these tumors to conventional therapies. In this model, a certain subset of tumor cells, with characteristics similar to normal stem cells, is capable of producing the variety of cell types, which constitute the bulk of a tumor. As these tumor cells have properties distinct from those constituting the bulk of the tumor, a different approach may be required to eradicate these residual cells within the brain. Here we outline the history behind the theory of GBM cancer stem-like cells, as they are now referred to. We will also discuss the implications of their existence on commonly held beliefs about GBM pathogenesis and how they might influence future treatment strategies.