Notch receptor signalling has been implicated in cell-fate decisions and differentiation in a variety of tissues. In an Advanced Online Publication in Nature Genetics Nicolas et al. define a tumour suppressor function for the mouse Notch1 gene (Nature Genetics, 18 February 2003, doi:10.1038/ng1099). As Notch1 is essential for embryonic development, they used a tissue-specific inducible gene-targeting approach to specifically delete the Notch1 gene in the skin. Notch1 ablation led to epidermal hyperproliferation and the development of basal cell carcinoma-like tumors. This was unexpected as active Notch signalling has been shown to cause tumors in other tissues. The Notch1-less mice were also susceptible to chemically induced carcinogenesis. Tumors lacking Notch1 were associated with decreased levels of the cyclin dependent kinase inhibitor p21Cip1 and elevated levels of the transcription factor Gli2 and components of the β-catenin/Wnt signaling pathway.