Methyltransferases are a class of enzymes that install a methyl (-CH3) substituent onto a variety of cellular substrates. Such methylation events, when decorating DNA or DNA-associated proteins (such as histones), are known to control gene transcription. Dysregulated methylation patterns (often resulting from over- or underexpressed methyltransferase enzymes) play a key role in silencing anti-apoptotic genes and activating pro- tumorigenic ones, leading to uncontrolled cellular growth, commonly known as cancer. Despite their relevance in disease, selective and cell-active inhibitors are currently available for only a handful of the ~150+ human methyltransferases. We hope to address this shortcoming by developing a universal chemoproteomic platform for profiling methyltransferase activity and inhibition in human cells and proteomes. To accomplish this goal, we have synthesized a small library of photoaffinity probes that target the cofactor binding site of methyltransferases. Using these probes, we will functionally characterize methyltransferases in a variety of normal and cancerous tissues, in an attempt to discover novel associations between methyltransferases and cancer. Second, by exploiting a recently discovered lead inhibitor of the cancer-associated enzyme NNMT, we will pursue the development of a selective and in-vivo active inhibitor of NNMT. We will further pursue selective covalent inhibitors for several cancer-associated methyltransferases. This work has the potential to change our understanding of the underlying molecular drivers of cancer pathogenesis, and will hopefully be translatable to eventual clinical applications.