Aberrant DNA methylation in the genome is found in almost all types of cancer and contributes to malignant transformation by silencing multiple tumour-suppressor genes, sometimes simultaneously. Therefore, deciphering the signature of DNA methylation in each tumour is required to better understand tumour behaviour and might be of benefit for clinical diagnostics and therapy. Recent technologies for high-throughput genome-wide DNA methylation analyses are promising and potent tools for epigenetic profiling. Since epigenetic therapy is now in clinical use or trials for several types of cancers, efficient epigenetic profiling is required. In this review, the current key technologies available to assess genome-wide DNA methylation are introduced and the implications of DNA methylation profiling in human cancers are discussed.