p53 is one of the most studied tumor suppressors in the cancer research field. Of note, over 50% of human tumors carry loss of function mutations, and thus p53 has been considered to be a classical Knudson-type tumor suppressor. From the functional point of view, p53 is a nuclear transcription factor to transactivate a variety of its target genes implicated in the induction of cell cycle arrest, DNA repair, and apoptotic cell death. In response to cellular stresses such as DNA damage, p53 is activated and promotes cell cycle arrest followed by the replacement of DNA lesions and/or apoptotic cell death. Therefore, p53 is able to maintain the genomic integrity to prevent the accumulation of genetic alterations, and thus stands at a crossroad between cell survival and cell death. In this paper, we describe a variety of molecular mechanisms behind the regulation of p53.