The functions of p53 most highly associated with the well-studied tumor suppressor are its abilities to induce cell cycle arrest and apoptosis in response to cellular stresses. Recent progress underscores that p53 is a multi-functional protein with activities that range beyond tumor suppression to normal homeostasis, metabolism, fertility and differentiation. A unifying theme of these studies is that p53 is first and foremost a transcription factor; and control of p53 protein stability determines its ability to carry out this task. There are an expanding number of E3-ubiquitin ligase proteins that target p53 for ubiquitin tagging and protein degradation. This review discusses these many effectors of p53 protein degradation, and our task is to provide some level of understanding as to their differences and their similarities. Further, we propose how some degree of specialization may be assigned to the E3-ligases, in their navigation toward a common goal of regulating p53 protein levels, and emphasize that better understanding of the mechanisms involved in E3-ligase functions is needed to further their potential as therapeutic targets.