Genome-wide analyses have been used to characterize the genetic landscapes of many cancers. One of the most frequent classes of genes found to be mutated in cancer is the epigenetic regulators, providing a link between genetic alterations and epigenetic changes in cancer. In addition, multiple studies have reported aberrant DNA methylation and hydroxymethylation patterns as well as histone modifications in cancer. The recognition of the mutuality between genetic and epigenetic aberrations in cancer and the reversible features of epigenetic changes provide a rationale for combining epigenetic therapy with conventional chemotherapy and form basis for the development of novel and targeted treatment modalities. In this chapter, we review aberrant DNA methylation and hydroxymethylation patterns in cancer and mutations in epigenetic regulators involved in DNA methylation and hydroxymethylation and discuss the effect of these aberrations on tumorigenesis.