Glioblastoma (GBM) is a highly malignant primary brain tumor known for its invasiveness and aggressive resistance to standard treatment. It is currently the most common primary brain tumor which is associated with a high mortality rate. Tumor initiating cells (TICs) are a subpopulation of GBM stem cells which are capable of self-renewal and apoptotic resistance, and are thought to account for GBMs aggressive nature. Recent efforts have focused on therapies which target key intracellular apoptotic pathways which may confer tumor resistance, such as Akt, p53, Bcl-2 family proteins, caspase family proteases, and more recently microRNAs. Research into microRNA's role in GBM has shown that microRNAs play a key regulatory role in the GBM apoptotic pathway, making it a potential therapeutic target. In this review we summarized the molecular mechanisms involved in the signaling pathways of human GBM TIC apoptosis and microRNAs, the contemporary treatments involving different members of the signaling cascade, and the future direction of GBM treatment strategies.