Normal healthy cells possess safeguard mechanisms that sense oncogenic signals and trigger anti-tumorigenic responses that limit the proliferative potential of cells harbouring active oncogenes. In particular, expression of the Ras oncogene in normal primary cells causes a cell-cycle arrest that involves the activation of the tumoursuppressor protein p53 . It has recently been reported that the tumour-suppressor p19^ARF can activate p53 (–). Here we show that p19^ARF in the mouse (the human homologue is called p14^ARF) is essential for the activation of p53 in response to oncogenic Ras. These results, together with the finding that p19^ARF does not mediate the activation of p53 by DNA damage, dissociate the activation of p53 into two pathways: one pathway is induced by DNA damage and is independent of p19^ARF, whereas the other pathway is induced by oncogenic Ras and is dependent on p19^ARF.