Glioblastoma multiforme (GBM) is a type of brain tumor that is notorious for its aggressiveness and invasiveness, and the complete removal of GBM is still not possible, even with advanced diagnostic strategies and extensive therapeutic plans. Its dismal prognosis and short survival time after diagnosis make it a crucial public health issue. Understanding the molecular mechanisms underlying GBM may inspire novel and effective treatments against this type of cancer. At a molecular level, almost all tumor cells exhibit telomerase activity (TA), which is a major means by which they achieve immortalization. Further studies show that promoter mutations are associated with increased TA and stable telomere length. Moreover, some tumors and immortalized cells maintain their telomeres with a telomerase-independent mechanism termed the “alternative lengthening of telomeres” (ALT), which relates to the mutations of the α-thalassemia/mental retardation syndrome X-linked protein (ATRX), the death-domain associated protein (DAXX) and H3.3. By means of the mutations of the telomerase reverse transcriptase (TERT) promoter and ATRX/DAXX, cancers can immortalize and escape cell senescence and apoptosis. In this article, we review the evidence for triggering GBM cell death by targeting telomerase and the ALT pathway, with an extra focus on a plant-derived compound, butylidene phthalide (BP), which may be a promising novel anticancer compound with good potential for clinical applications.