The article reviews the complex regulation of p53 ubiquitination and degradation, challenging the conventional view that Mdm2 is the sole or primary E3 ubiquitin ligase responsible for p53 turnover. It highlights the roles of other E3 ligases such as MdmX, HAUSP, ARF-BP1, COP1, and Pirh2 in p53 regulation. The article also discusses the reversible nature of p53 ubiquitination, the involvement of deubiquitinating enzymes like HAUSP, and the dynamic regulation of Mdm2 levels. It suggests that Mdm2 may not be essential for p53 turnover in unstressed cells and proposes a model where Mdm2 controls p53 levels and activities during stress responses, while other E3 ligases maintain low steady-state p53 levels in normal cells. The evolutionary conservation of ARF-BP1 and the potential role of Mdm2 in cell survival under stress are also explored.The article reviews the complex regulation of p53 ubiquitination and degradation, challenging the conventional view that Mdm2 is the sole or primary E3 ubiquitin ligase responsible for p53 turnover. It highlights the roles of other E3 ligases such as MdmX, HAUSP, ARF-BP1, COP1, and Pirh2 in p53 regulation. The article also discusses the reversible nature of p53 ubiquitination, the involvement of deubiquitinating enzymes like HAUSP, and the dynamic regulation of Mdm2 levels. It suggests that Mdm2 may not be essential for p53 turnover in unstressed cells and proposes a model where Mdm2 controls p53 levels and activities during stress responses, while other E3 ligases maintain low steady-state p53 levels in normal cells. The evolutionary conservation of ARF-BP1 and the potential role of Mdm2 in cell survival under stress are also explored.