DNA methylation, occurring at cytosines in CpG dinucleotides, is a potent mechanism of transcriptional repression. Proper genomic methylation -patterns become profoundly altered in cancer cells: both gains (hypermethylation) and losses (hypomethylation) of methylated sites are observed. Although DNA hypomethylation is detected in a vast majority of human tumors and affects many genomic regions, its role in tumor biology remains elusive. Surprisingly, DNA hypomethylation in cancer was found to cause the aberrant activation of only a limited group of genes. Most of these are normally expressed exclusively in germline cells and were grouped under the term "cancer-germline" (CG) genes. CG genes represent unique examples of genes that rely primarily on DNA methylation for their tissue-specific expression. They are also being exploited to uncover the mechanisms that lead to DNA hypomethylation in tumors. Moreover, as CG genes encode tumor-specific antigens, their activation in cancer highlights a direct link between epigenetic alterations and tumor immunity. As a result, clinical trials combining epigenetic drugs with anti-CG antigen vaccines are being considered.