The current concept of tumourigenesis holds that cancer results from the progressive acquisition of mutations that endow affected cells with selective growth advantages by activating multiple processes including intrinsic mitogenic and pro-survival pathways. Constitutive activation of the Hedgehog (HH)/GLI signalling cascade has recently been implicated in the growth of a number of human malignancies ranging from semi-malignant tumours of the skin to highly aggressive cancers of the brain, lung, pancreas and prostate. This review focuses on the role of the GLI zinc finger transcription factors, which mediate Hedgehog signalling at the distal end of the pathway. We summarise recent data on the mechanisms by which latent GLI proteins are activated in response to stimulation of Hedgehog signalling. Based on the identification of a growing number of direct GLI target genes, we propose that HH-driven tumourigenesis relies on multiple cellular processes such as promotion of G1/S phase progression, enhancement of cell survival by providing anti-apoptotic cues, increase in metastatic potential of Hedgehog responsive cells, and activation of potential tumour stem cells. In view of the critical role of GLI genes in Hedgehog-associated cancers, strategies that aim at interfering with GLI function are likely to represent efficient approaches in future targeted cancer therapy.