In this review the current state‐of‐the‐art of S‐adenosylmethionine (SAM)‐dependent methyltransferases and SAM are evaluated. Their structural classification and diversity is introduced and key mechanistic aspects presented which are then detailed further. Then, catalytic SAM as a target for drugs, and approaches to utilise SAM as a cofactor in synthesis are introduced with different supply and regeneration approaches evaluated. The use of SAM analogues are also described. Finally O‐, N‐, C‐ and S‐MTs, their synthetic applications and potential for compound diversification is given.