The presence of hypoxia within a tumor is associated with poor clinical outcome, which is often exacerbated by loss of the tumor suppressor p53. In the presence of functional p53, hypoxic conditions promote apoptosis; however, the p53-dependent genes that mediate this process are not well understood. In this issue of the JCI, Leszczynska and colleagues identify a p53-dependent six-gene signature that is specifically induced in hypoxia and mediates apoptosis. In patients with a variety of cancers, downregulation of this gene signature was associated with poor clinical outcome. Induction of p53-dependent apoptosis under hypoxia was mediated by AKT inhibition, and treatment with the combination of an AKT inhibitor and ionizing radiation decreased tumor size in a p53-deficient xenograft model more substantially than either single-agent treatment. The results of this study provide important insight into p53-mediated apoptosis under hypoxia and suggest that AKT inhibition has therapeutic potential for inducing apoptosis in hypoxic, p53-deficient cancers.