Methyltransferases represent a class of enzyme responsible for the modification of biomolecules through the transfer of individual methyl units. The cofactor, S-adenosyl-L-methionine (SAM), serves as the methyl source for the vast majority of these enzyme-catalyzed reactions. These transformations have broad implications for many biological processes, ranging from the biosynthesis of essential cellular metabolites and pharmaceutically relevant natural products to the regulation of gene expression and protein function through the modification of nucleic acids and polypeptides. In addition, the malfunction of methyltransferase activity has been strongly implicated in a number of disease states including developmental disorders and carcinogenesis. As such, there has been significant effort in recent years to better understand these enzymes, their substrates, and the biological effects associated with their activity. Despite increased interest, the study of these processes has proven difficult using traditional biochemical or genetic techniques. In light of this, the research described herein has been aimed at the development of novel chemical tools and approaches for the study of these enzymes, with an emphasis on protein methyltransferases (PMTs). This research can be broadly categorized into two main focuses: (i) the implementation of Bioorthogonal Profiling of Protein Methylation (BPPM), in which substrates of specific PMTs are determined through the use of engineered enzymes, SAM analogues and bioorthogonal chemistry; and (ii) the development of a selenium-based SAM analogues, one of which has shown broad compatibility toward a wide variety of wild-type enzymes including: protein, nucleic acid and small-molecule methyltransferases. With these tools in hand, novel substrates for the G9a and GLP1 protein lysine methyltransferases have been identified, and a versatile selenium-based SAM mimic has demonstrated potential as a useful tool for the enzymatic functionalization of proteins and small molecules.