p53, a critical tumor suppressor, is activated by various cellular stresses to prevent and repair damages that can lead to tumor development. In response to these stresses, p53 activation can cause very serious cellular effects including permanent cell cycle arrest and cell death. p53 must therefore be very tightly regulated to avoid unnecessary pathological effects. The homologs MDM2 and MDMX have been shown to be the major, essential negative regulators of p53. In normal cells, MDM2 and MDMX suppress p53 activity, but in the event of cellular stress, they themselves must be inhibited so that p53 may respond to the stress. MDM2 and MDMX are known to bind together, and play multifaceted, non-redundant roles in modulating p53 protein activity. Recently, evidence has emerged showing that MDM2 and MDMX most effectively inhibit p53 as a complex, and possibly play non-redundant roles because they must function as one to control p53. In this review, we give an overview of MDM2 and MDMX and discuss a few ways in which they are modified so that p53 may be activated. Lastly, we discuss the non-redundant roles of MDM2 and MDMX and how it is important to investigate the effect on the complex as a whole when investigating either protein.