Methyltransferases (MTases) play an important role in the functioning of living systems, catalyzing the methylation reactions of DNA, RNA, proteins, and small molecules, including endogenous compounds and drugs. Many human diseases are associated with disturbances in the functioning of these enzymes; therefore, the study of MTases is an urgent and important task. Most MTases use the cofactor S-adenosyl-L-methionine (SAM) as a methyl group donor. SAM analogs are widely applicable in the study of MTases: they are used in studies of the catalytic activity of these enzymes, in identification of substrates of new MTases, and for modification of the substrates or substrate linking to MTases. In this review, new synthetic analogs of SAM and the problems that can be solved with their usage are discussed.