Normal tissues are organized in a hierarchical model, whereas at the apex of these hierarchies reside stem cells (SCs) capable of self-renewal and of producing differentiated cellular progenies, leading to normal development and homeostasis. Alike, tumors are organized in a hierarchical manner, with cancer SCs residing at the apex, contributing to the development and nourishment of tumors. p53, the well-known ‘guardian of the genome’, possesses various roles in embryonic development as well as in adult SC life and serves as the ‘guardian of tissue hierarchy’. Moreover, p53 serves as a barrier for dedifferentiation and reprogramming by constraining the cells to a somatic state and preventing their conversion to SCs. On the contrary, the mutant forms of p53 that lost their tumor suppressor activity and gain oncogenic functions serve as ‘inducers of tissue anarchy’ and promote cancer development. In this review, we discuss these two sides of the p53 token that sentence a tissue either to an ordered hierarchy and life or to anarchy and death. A better understanding of these processes may open new horizons for the development of new cancer therapies.