The enzymes that regulate histone methylation states and the protein domains that recognize methylated histone residues have been implicated in a number of human diseases, including cancer, as a result of their ability to affect transcriptional changes by altering chromatin structure. These proteins are recognized as potential therapeutic targets for the treatment of diseases associated with epigenetic disruption; however, few inhibitors of their activity have been identified. The majority of histone demethylase and methyltransferase enzyme inhibitors have been discovered on the basis of their structural similarity to substrates or known inhibitors of enzymes with analogous mechanisms. The general lack of potency and specificity of these compounds indicates that novel chemotypes are needed to address the large number of recently discovered histone-modifying enzymes. High-throughput screening (HTS) allows rapid testing of chemically diverse small molecule libraries, provided assays amenable to HTS exist. Here we review the biochemical and cellular assays available for testing the proteins and enzymes that regulate histone methylation. Progress in the development of high-throughput, sensitive, and robust assays will enable discovery of small molecules for epigenetic therapy.