Do tumours arise from stem cells, or are they derived from more differentiated cells that, for some reason, begin to recapitulate developmental programmes? Inappropriate activation of the Sonic hedgehog-Gli signalling pathway occurs in several types of tumour, including those of the brain and the skin. Studies in these and other systems suggest that inappropriate function of the Gli transcription factors in stem or precursor cells might lead to the onset of a tumorigenic programme and that these factors are prime targets for anticancer therapies.