The disruption and alteration of genomic methylation patterns is a hallmark of cancer and other disease states. Understanding and characterizing genome-wide methylation will have a profound effect on our understanding of tumorigenesis and provide novel avenues for therapy. This chapter serves to describe techniques that examine genome-wide methylation patterns including luminometric methylation assay, restriction landmark genome scanning, and the cytosine extension assay, which utilize methylation-sensitive restriction enzymes. Additional techniques such as nucleotide separation assays (nearest neighbor analysis and high-performance capillary electrophoresis) and the infinium methylation assay are discussed. These techniques allow for the determination of changes in global methylation levels, as well as regional changes in methylation throughout the genome.