A cohort of genes associated with embryonic stem (ES) cell behaviour, including NANOG, are expressed in a number of human cancers. They form an ES‐like signature we first described in glioblastoma multiforme (GBM), a highly invasive and incurable brain tumour. We have also shown that HEDGEHOG‐GLI (HH‐GLI) signalling is required for GBM growth, stem cell expansion and the expression of this (ES)‐like stemness signature. Here, we address the function of NANOG in human GBMs and its relationship with HH‐GLI activity. We find that NANOG modulates gliomasphere clonogenicity, CD133⁺ stem cell cell behavior and proliferation, and is regulated by HH‐GLI signalling. However, GLI1 also requires NANOG activity forming a positive loop, which is negatively controlled by p53 and vice versa. NANOG is essential for GBM tumourigenicity in orthotopic xenografts and it is epistatic to HH‐GLI activity. Our data establish NANOG as a novel HH‐GLI mediator essential for GBMs. We propose that this function is conserved and that tumour growth and stem cell behaviour rely on the status of a functional GLI1‐NANOG‐p53 network.