The transcription factor TP53 (also called TRP53 in mice or p53 in general and used hereafter) is essential to prevent the development of cancer. Upon activation in response to diverse stresses, such as oncogene expression, DNA damage or nutrient deprivation, p53 orchestrates diverse cellular responses, most prominently cell cycle arrest/cell senescence and cell death by apoptosis, by directly or indirectly activating ~500 target genes. It has been postulated that cell survival vs cell death after p53 activation is decided by selective transcriptional induction of either of the direct p53 target genes, p21 critical for cell cycle arrest/senescence, or Puma/Bbc3 to initiate apoptosis. Our analysis using mice co-expressing transcriptional reporters for both p21 and Puma demonstrated that single cells induce expression of both the initiators of cell cycle arrest and for apoptosis regardless of whether they will survive or die. Thus, factors other than induction of p21 and Puma must decide cell outcome after p53 activation. Our RNA sequence and functional analyses of several cell types revealed that the genes for anti-apoptotic BCL-XL and MCL-1 are transcriptionally up-regulated in cells that survive after p53 activation. Increasing BCL-XL or MCL-1 allowed cells to survive that would normally die after p53 activation. Conversely, blunting the pro-survival functions of BCL-XL and/or MCL-1 pharmacologically, led to the death of cells that normally survive after p53 activation. These findings reveal the mechanism by which cell fate – survival or death – is decided after p53 activation and identify a strategy how anti-cancer drug induced cell cycle arrest/senescence in malignant cells can be converted into apoptotic death to enhance therapeutic impact.