Recent advances in epigenetic research have produced new high-throughput technologies for the analysis of cytosine methylation patterns and histone modification marks that provide insight into the structure and function of the human genome. It is towards the goal of characterizing the human leukemia and lymphoma methylomes that Taylor and colleagues developed a novel approach for conducting multisample, multigene, ultradeep bisulfite sequencing analysis of DNA methylation patterns in clinical samples using a recently developed massively parallel sequencing-by-synthesis method (454 sequencing). They demonstrated differential methylation patterns between diseases and detected a progressive spreading of methylation from the periphery towards the center of select CpG islands in acute leukemia and follicular lymphoma samples. This new generation of methylome sequencing will provide digital profiles of aberrant DNA methylation for individual human cancers and offers a robust method for the epigenetic classification of tumor subtypes. For details, see the article by Taylor and colleagues on page 8511 of this issue.