The p53 tumor suppressor pathway is a key mediator of stress response that protects the organism from accumulating genetically altered and potentially cancerous cells by inducing growth arrest or apoptosis in damaged cells. However, under certain stressful conditions, p53 activity can result in massive apoptosis in sensitive tissues, leading to severe pathological consequences for the organism. One such situation is anticancer therapy that is often associated with general genotoxic stress, leading to p53-dependent apoptosis in the epithelia of the digestive tract and in the hematopoietic system. A chemical inhibitor of p53, capable of suppressing p53-mediated apoptosis, was shown to protect mice from lethal doses of gamma-radiation, making pharmacological suppression of p53 a perspective therapeutic approach to reduce the side-effects of cancer treatment. There are other situations, besides anti-cancer therapy, when humans are exposed to stressful conditions known to involve p53 activation, which, in extreme cases, could result in the development of life-threatening diseases. Here we review the experimental evidence on the role of p53 in tissue injuries associated with hypoxia (heart and brain ischemias) and hyperthermia (fever and burns), comparing these pathologies with the consequences of genotoxic stress of cancer treatment. The accumulated information points to the involvement of p53 in the generation of the pathological outcome of the above stresses, making them potential targets for the therapeutic application of p53 inhibitors.