Aberrant distribution of cytosine methylation in cancer has been linked to deregulation of gene expression and genomic instability. DNA methylation changes in cancer include both hyper and hypomethylation, and the precise localization of these changes is directly related to the impact they have on gene regulation. To determine both the localization and extent of DNA methylation status under different conditions, we have developed the HpaII tiny fragment enrichment by ligation-mediated PCR (HELP) assay, a microarray-based technique that allows the simultaneous interrogation of the methylation status of hundreds of thousands of CpG dinucleotides. The HELP assay allows methylation levels throughout the genome to be accurately determined so that the epigenetic state of leukemia cells can be identified, compared, and contrasted.