DNA methylation is an important and reversible epigenetic modification, which regulates genomic stability and cellular plasticity. Faithful DNA methylation is essential for mammalian development and health, and perturbation of methylation dynamics contributes to the development of disease, including cancer. The discovery and validation of the biological indicators (biomarkers) for human cancers are essential steps in the development of methods for accurate subtype classification and outcome prediction in clinic oncology. While genetics (SNP, LOH and mutation) and expression profiling (mRNA and protein) of biomarkers have been extensively assessed for cancer diagnosis and prognosis, the potential for using epigenetic fingerprints for early diagnosis and outcome prediction in clinic oncology propels the exploration of using DNA methylation as a biomarker for cancer prognosis. Both the promises and challenges to realizing the clinical utility of the DNA methylation in cancer management are discussed in this review.