In the two decades since the discovery of altered gene methylation in cancer, epigenetic alterations have been linked to gene activation, gene silencing, chromosomal instability, and most recently genomic imprinting. These discoveries offer the promise of novel chemotherapeutic and chemopreventive approaches to cancer. Recent data from our laboratory suggest that both gains and losses of methylation may be important mechanisms for the epigenetic instability of cancer. In particular, increased methylation affecting CTCF- and BORIS-binding sites of a differentially methylated region upstream of H19, and alternatively loss of methylation at distinct regulatory sites, is linked to loss of imprinting, depending on tumor type. We also found an important role for specific methyltransferases in maintenance of normal imprinting in tumor cells. Finally, we found a large number of novel targets for normal epigenetic modification and alteration in cancer, including normally methylated CpG islands throughout the genome.