p53 imposes a critical barrier against cancer development. Transcriptional regulation of target genes controlling cell death, (Puma, Noxa), cell cycle arrest and senescence, (p21), have widely been thought to be critical for p53-mediated tumour suppression. Two recently published papers questioned this view. p53 knock-in mice carrying mutations affecting DNA binding were generated, and while exhibiting impaired ability to transcribe Puma, Noxa and p21, both retained wild-type p53 tumour suppressive activity (Brady et al., 2011; Liu et al., 2012). Although p53-mediated up-regulation was impaired, expression of these regulators was not completely abrogated. To determine definitively whether expression of these genes plays an essential role in p53’s tumour suppressive activity, we generated p21-/-puma-/-noxa-/- mice. In response to DNA damage, p21-/-puma-/-noxa-/- primary cells exhibit resistance to cell death, cell cycle arrest and senescence, comparable to p53-/-cells. Remarkably, aged p21-/-puma-/-noxa-/-mice showed no signs of spontaneous tumour formation, demonstrating transcriptional induction of apoptosis, cell cycle arrest and senescence is not essential for p53’s ability to prevent tumour development. An important challenge remains to define which p53-activated pathways impose the critical barrier to tumorigenesis. Interestingly we show early evidence that p53-mediated coordination of DNA repair is retained within p21-/-puma-/-noxa-/- mice, potentially suggesting a role for this process in p53’s tumour suppressive function.