To illustrate the relevance of the interplay between MDM2/MDMX and RB and p53 in human cancers, we will give an overview of progress in the field, the similarities and differences in the regulation of these important tumor suppressors through MDMX and MDM2, and finally analyze the crosstalk between the p16Ink4a/RB/ E2F and the p14ARF/p53/MDM2/MDMX pathways. Here, MDM2 is linked to cancer.