Most tumours are heterogeneous at the cellular and (epi)genetic levels. This heterogeneity has been proposed to be responsible for tumour progression, metastasis and resistance to therapy. Our goal is to understand the contribution of the different tumour cell populations and genetic alterations to cancer progression and response to therapy. We do that by combining genetic lineage tracing, clonal analysis, imaging techniques, tumour organoid cultures and functional experiments in vivo and in vitro. We use the most frequent human cancer – basal cell carcinoma – and one of the most common pediatric cancers – medulloblastoma – as the models for our studies. Both types of cancer arise upon the constitutive activation of the Hedgehog signalling pathway.