S-Adenosylmethionine (SAM) is a well-known universal methyl donor, but has a myriad of other functions in cellular synthesis, maintenance, and repair. Via the transsulfuration pathway it controls synthesis of glutathione, while decarboxylation of SAM fuels the polyamine pathway. Glutathione is the main antioxidant in the cell, while polyamines coat negative backbones of e.g. DNA, RNA, and proteins. In this way, SAM controls the redox balance, as well as bending, opening up, and folding of macromolecules, with a concomitant impact on replication, transcription, translation, DNA repair and chromatin (re)modeling. SAM is involved in ancient RNA metabolism via its effect on transcription and translation via small RNA riboswitches. Finally, ‘radical SAM’ enzymes with SAM-dependent iron–sulfur (FeS) clusters perform difficult biochemical reactions in microorganisms and eukaryotic cells, including the energy-generating organelles, mitochondria and chloroplasts. These enzymes perform vital functions in the synthesis and use of building blocks for DNA, RNA, proteins, vitamins, antibiotics, toxins, and in the formation or removal of radicals. SAM is important in mitochondrial functioning, intra- and extra-cellular communication, as well as the establishment and maintenance of the microbiome, which makes it an attractive target for new pharmacological intervention strategies to improve health and longevity.