Many cancers become resistant to chemotherapeutic drugs thanks to loss of the p53 protein, which promotes cell cycle arrest and apoptosis in response to certain drugs. Metastatic melanomas are unusual in that, despite their chemoresistance, they retain functional p53. In the January 11 Nature, Soengas et al. find that these melanomas still lose the p53 pathway thanks to deletion and methylation of the p53 effector Apaf-1 (Nature 2001, 409:207-211). The Apaf-1 locus shows over 40% loss of heterozygosity in melanomas, and in these cells the remaining Apaf-1 gene is no longer expressed. Expression and chemoresistance can be reactivated by addition of either a methylation inhibitor or a functional Apaf-1 gene.