Restriction landmark genomic scanning (RLGS) has been used to study DNA methylation in cancer for nearly a decade. The strong bias of RLGS for assessing the methylation state of CpG islands genome wide makes this an attractive technique to study both hypo- and hypermethylation of regions of the genome likely to harbor genes. RLGS has been used successfully to identify regions of hypomethylation, candidate tumor suppressor genes, correlations between hypermethylation events and clinical factors, and quantification of hypermethylation in a multitude of malignancies. This review will examine the major uses of RLGS in the study of aberrant methylation in cancer and discuss the significance of some of the findings.