Histone methyltransferases (HMTs) are enzymes that catalyze the methylation of lysine or arginine residues of histone proteins, a key post-translational modification (PTM). Aberrant expression or activity of these enzymes can lead to abnormal histone methylation of cancer-related genes and thus promote tumorigenesis. Histone methyltransferases have been implicated in chemotherapeutic resistance and immune stimulation, making these enzymes potential therapeutic targets of interest, and chemically targeting these proteins provides an avenue for novel drug development in cancer therapy. This Review aims to discuss the evolution of chemical approaches that have emerged in the past five years to design probes targeting these enzymes, including inhibition through noncovalent inhibitors, covalent inhibitors, and targeted protein degradation through proteolysis targeting chimeras (PROTACs). This Review also highlights how these compounds have been used to study the myriad of HMT functions in cancer progression and treatment response. The recent advancement of some of these drugs into human clinical investigation and even to regulatory approval highlights HMTs as a promising class of targets for chemical intervention and novel therapy development.