In contrast to classical mutations, DNA methylation is a mechanism of changing the base sequence without altering the coding function of a gene. The interplay between this epigenetic modification and classical mutations plays an important role in tumorigenesis. Global genomic hypomethylation has been associated with the induction of chromosomal instability, which is commonly seen in solid tumors and multiple myeloma. De novo methylation of CpG islands on the promoter region may contribute to the progressive inactivation of growth-inhibitory genes resulting in the clonal selection of cells with growth advantage. Recently, alteration of p16 and p15 solely by hypermethylation has been detected in high frequencies hitherto unreported in multiple myeloma (MM). Hypermethylation of p16 has been shown to be associated with plasmablastic disease (p=0.026) in primary MM and transcriptional silencing of p16 and p15 has also been found to correlate with hypermethylation of these genes in MM-derived cell lines. Our results in studies with cell lines and primary MM support the fact that hypermethylation of p16 and p15 plays an important role in MM tumorigenesis. Because of its high frequency, the presence of hypermethylation of p16 may prove to be a useful tumor marker for the majority of MM patients. Promoters silenced by methylation can be reactivated by treatment with the demethylating agent 5-aza-2'deoxycytidine. The reversibility of this epigenetic inactivation of the p16 and p15 genes in MM may also provide a broad clinical application in the development of new therapeutic interventions in this uniformly fatal form of cancer.