Glioblastomas (GBM) are the most aggressive and lethal primary astrocytic tumors in adults, with very poor prognosis. GBMs display significant heterogeneity within the tumor mass, among which a small sub-population of tumor cells with stem-like properties (GSLCs) is responsible for tumor growth, resistance to therapies and tumor recurrence. The high resistance of GSLCs to chemotherapies have been attributed to their capacity to enter quiescence. Quiescence is a reversible cell-cycle arrest which allows cancer stem-like cells to evade killing following therapies. By combining bioluminescent Ca2+-imaging and RNAseq analysis we explored how proliferating and quiescent GSLCs maintain Ca2+ homeostasis and showed that the remodelling of the Ca2+ homeostasis and the reshaping of mitochondria might favour quiescent GSLCs’ survival and aggressiveness in glioblastoma. The importance of the role played by Ca2+ in these last processes lead us to search for Ca2+-binding proteins which can relay Ca2+ signaling to gene expression. KCNIPs (potassium channel-interacting proteins), which constitute the class E of Ca2+ sensor family can control gene transcription directly by binding, via a Ca2+-dependent mechanism, to specific DNA sites on target genes. The presence of putative binding sites for KCNIPs on genes associated with unfavorable outcome for GBM patients suggests that KCNIP proteins may contribute to the alteration of the expression of these prognosis genes. This presentation will also discuss the role of this multifunctional Ca2+ sensors in the regulation of Ca2+ homeostasis in glioblastoma and how Ca2+ via KCNIP proteins may affect prognosis genes expression in GBM.