Notch 1 to 4 and the p53 clan, comprising p53, p63 and p73 plus numerous isoforms thereof, are gene transcription regulators that are critically involved in various aspects of cell differentiation, stem cell maintenance and tumour suppression. It is thus perhaps no surprise that extensive crosstalk between the Notch and p53 pathways is implemented during these processes. Typically, Notch together with p53 and even more so with transactivation competent p63 or p73, drives differentiation, whereas Notch combined with transactivation impaired p63 or p73 helps maintain undifferentiated stem cell compartments. With regard to cancer, it seems that Notch acts as a tumour suppressor in cellular contexts where Notch signalling supports p53 activation and both together can bring on its way an anti‑proliferative programme of differentiation, senescence or apoptosis. In contrast, Notch often acts as an oncoprotein in contexts where it suppresses p53 activation and activity and where differentiation is unwanted. It is no accident that the latter pathways—the inhibition by Notch of p53 and differentiation—are operative in somatic stem cells as well as in tumour cells.