Aberrant DNA methylation of CpG islands (CGIs) is a common alteration during malignant transformation that leads to the abnormal silencing of tumor suppressor genes and plays a role in disease initiation and progression. The main focus of the present work is the implementation of methodologies to identify epigenetic marker genes that can be used for the diagnosis as well as for the targeted treatment of tumors. The newly developed methyl CpG immunoprecipitation (MCIp) technique allows for the unbiased genome-wide profiling of CpG methylation in DNA samples where quantity is limited. The comprehensive analysis identified a large array of CGIs that are previously unrecognized targets of hypermethylation in acute myeloid leukemia (AML). Furthermore, the molecular mechanisms controlling the methylation status of CpG islands in normal and malignant cells were analyzed and factors were identified that are responsible for maintaining or establishing methylated states of CGIs in health and disease as well as for de novo methylation in cancer.