The abnormal expression of protein methyltransferase (PMT) has been linked with many diseases such as diabetes, neurological disorders, and cancer. S-Adenyl-l-methionine (SAM) is a universal methyl donor and gets converted to S-adenyl-l-homocysteine (SAH), an endogenous competitive inhibitor of SAM. Initially developed SAM/SAH mimetic nucleoside analogues were pan methyltransferase inhibitors. The gradual understanding achieved through ligand-receptor interaction paved the way for various rational approaches of drug design leading to potent and selective nucleoside inhibitors. The present perspective is based on the systematic evolution of selective SAM-competitive heterocyclic non-nucleoside inhibitors from nucleoside inhibitors. This fascinating transition has resolved several issues inherent to nucleoside analogues such as poor pharmacokinetics leading to poor in vivo efficacy. The perspective has brought together various concepts and strategies of drug design that contributed to this rational transition. We firmly believe that the strategies described herein will serve as a template for the future development of drugs in general.