Discovered in 1987 and 1997 respectively, Mdm2 and MdmX represent two critical cellular regulators of the p53 tumor suppressor. This chapter reviews each from initial discovery to our current understanding of their deregulation in human cancer with a focus on how each regulator impacts p53 function. While p53 independent activities of Mdm2 and MdmX are noted the reader is directed to other reviews on this topic. The chapter concludes with an examination of the various mechanisms of Mdm-deregulation and an assessment of the current therapeutic approaches to target Mdm2 and MdmX overexpression.