To probe the roles of MDM2 and MDM4 in TP53 regulation in cancer cells, we selected efficient and specific dsRDC-modified siRNAs targeting MDM2 and MDM4. Individual and combined knockdown of MDM2 and MDM4 revealed their roles in TP53 inactivation in wt TP53 cancer cells with different patterns of MDM2 and MDM4 expression, which provided us with a rationale for the selection of MDM2 and MDM4 as targets in TP53 restoration therapy of cancers. Here, MDM4 is linked to cancer.