Significance It has long been observed that activation of p53 can yield two main cell fates: either apoptotic cell death or cell cycle arrest. However, what determines this cell fate remains to be fully elucidated. Here we show that the state of mitochondrial priming prior to activation of p53 can determine cell fate. Highly primed cells commit to apoptosis, while less-primed cells commit to cell cycle arrest. We show that modulation of priming in either direction can alter cell fate; increasing priming in poorly primed cells yields apoptosis, while decreasing priming in highly primed cells yields arrest. Drugs that increase priming enforce an apoptotic fate, suggesting a p53-independent strategy for augmenting efficacy of cancer chemotherapy drugs that kill via p53.