p53 is a crucial regulator of cell response to DNA damage. MDM4 and MDM2 are the two main negative regulators of p53 activity. Upon DNA damage, their constraint is released and p53 becomes activated and exerts its safeguard function by arresting cell growth or by killing excessively damaged cells. Under these conditions, increasing data suggest that MDM4 and MDM2 play novel roles. In this respect, we recently published that MDM4 exerts a positive activity towards p53 mitochondrial apoptosis. We observed that a fraction of MDM4 stably localizes at the mitochondria where upon lethal stress conditions, promotes the mitochondrial localization of p53 phosphorylated at Ser46 (p53Ser46(P)) and facilitates its binding to BCL2, cytochrome C release and apoptosis. Most importantly, we observed a correlation of MDM4 expression with cisplatin-resistance in a group of human ovarian cancers suggesting that MDM4 proapoptotic activity may have in vivo relevance. Here, we discuss about these and some new findings and compare them with previous data trying to settle some apparent contradictions. In addition, this review discusses the potential relevance of our data to the field of human cancer.