A high proportion of malignant melanomas express wild-type p53 that is often inactive. Xin Lu and colleagues have found that most malignant melanoma cell lines with wild-type p53 have high levels of phosphorylated iASPP in the nucleus. iASPP interacts with p53 and inhibits apoptosis, and these authors found that iASPP is phosphorylated by cyclin B1–cyclin-dependent kinase 1 (CDK1). This prevents dimerization of iASPP and enables the monomeric phosphorylated form of iASPP to accumulate in the nucleus and to interact with p53. Previous studies have shown that wild-type p53 activity can be increased in cancer cells through the use of inhibitors of MDM2, a ubiquitin ligase that binds and ubiquitylates p53, which can result in its degradation. Inhibition of iASPP phosphorylation and MDM2 activity using small-molecule inhibitors resulted in apoptosis and growth suppression of wild-type p53 melanoma cell lines. Moreover, this approach combined with the BRAF inhibitor vemurafenib substantially reduced the growth of human melanoma xenografts with wild-type p53 and a BRAF-V600E mutation.