Being most well-known tumor suppressor that is inactivated in tumors more frequently than any other gene, p53 has been recently recognized as a major player in a variety of pathologies caused by acute stresses of tissues that is responsible for massive cell loss from apoptosis. This created a controversial situation when effective treatment of acute pathology requires inhibition of a major cancer preventive factor that has been traditionally viewed as a target for therapeutic activation. Here we briefly review specific aspects of this problem and discuss the ways of its pharmacological resolution based on detailed knowledge of molecular mechanisms of p53 regulation and activity.