In eukaryotic genomes, DNA is wrapped around histone proteins to form repeating units known as nucleosomes, which are further condensed into chromosomes. This high level of structure creates a barrier to transcription, which is maintained or reversed via modifications to the N-terminal tails of histone proteins. Histone lysine methyltransferases catalyze the mono-, di-, and/or trimethylation of lysine residues within histone tails; the methylation state of histone tails has profound effects on transcription. For example, polycomb repressive complex 2 (PRC2) is responsible for regulating the methylation status of histone 3 lysine 27 (H3K27) via the catalytic subunit EZH1 or EZH2, and the lysine methyltransferase G9a catalyzes mono- and dimethylation of histone 3 lysine 9 (H3K9). These methyltransferases are of great interest, because trimethylation of H3K27 and dimethylation of H3K9 are transcriptionally repressive marks that play a key role in the progression of many diseases. Chemical probes that selectively inhibit the methyltransferase of interest are valuable tools to drive further understanding of the biological function of these proteins and assess their potential as therapeutic targets. Here we describe the design, development, and application of chemical probes and tools for both EZH1 and EZH2 (UNC1999), and G9a (UNC0965). UNC1999 was the first orally bioavailable chemical probe of EZH1 and EZH2. This discovery led to the design of a biotinylated tool (UNC2399), which allows for selective chemiprecipitation of EZH1 and EZH2 from cellular lysates. UNC1999 is also the most panactive EZH1 and EZH2 chemical probe to date. We exploited this feature to demonstrate the potential therapeutic application of small molecule inhibition of both EZH1 and EZH2 in MLL-rearranged leukemia. Lastly, we detail the in vitro and ex vivo use of a biotinylated G9a inhibitor (UNC0965) in a chemical-based chromatin immunoprecipitation (chem-ChIP) assay for studying G9a chromatin occupancy.