DNA methylation of promoter CpG islands is strongly associated with gene silencing and is known as a frequent cause of loss of expression of tumor suppressor genes, as well as other genes involved in tumor formation. DNA methylation of driver genes is very likely outnumbered by the number of methylated passenger genes, though these can be useful as tumor markers. Much of what is known about the importance of DNA methylation in cancer was gained through small- and moderate-scale analysis of gene promoters and tumor samples. A much better understanding of the role of DNA methylation in cancer, either as a marker of disease or as an active driver of tumorigenesis, will likely be gained from genome-wide studies of this modification in normal and malignant cells. This goal has become more attainable with the recent introduction of large-scale genome analysis methodologies and these have been modified to allow for investigation of DNA methylation. Several research groups have been formed to coordinate efforts and apply these methodologies to decipher the methylome of healthy and diseased tissues. In this article we review technological advances in genome-wide methylation profiling.