Telomerase de-regulation is long known to be one of the causal factors in cancer initiation and progression. It is repressed in adult normal cells and is known to be activated in ~90% of cancers. However underlying mechanisms that trigger reactivation have remained poorly understood. Our recent findings show the intriguing possibility that DNA secondary structure G-quadruplex forms regulate the epigenetic state of the telomerase promoter, and thereby expression of telomerase remains under control. The relevance of this mechanism is underscored through two clinical mutations – found in high frequency in a large number of melanoma glioblastoma patients - that disrupt G-quadruplex formation. Ligand-induced re-stabilization of the promoter G-quadruplex restored the epigenetic state and re-suppressed telomerase in cancer cells, substantiating the newly revealed mechanistic understanding. Overall, this brings forth two novel points. First, shows the use of G-quadruplex-stabilizing ligands in regulating hTERT expression via restoration of the transcription factor binding site in neoplastic, hTERT-reactivated cancer cells. Second, it shows the possibility for development of novel G-quadruplex targeting epigenetic drugs that may work in telomerase regulation.