SAM (S-adenosylmethionine, also known as AdoMet) is well known as the methyl donor for the majority of methyltransferases that modify DNA, RNA, histones and other proteins, dictating replicational, transcriptional and translational fidelity, mismatch repair, chromatin modelling, epigenetic modifications and imprinting, which are all topics of great interest and importance in cancer research and aging. In total, 15 superfamilies of SAM-binding proteins have been identified, with many additional functions varying from methylation of phospholipids and small molecules such as arsenic to synthesis of polyamines or radical formation. SAM is regenerated from demethylated SAM via the methionine cycle, which involves folate. Imbalance of this cycle in humans, e.g. through folate shortage via dietary insufficiency, alcohol abuse, arsenic poisoning or hereditary factors, leads to depletion of SAM and human disease. In addition to its role as a methyl donor to modification enzymes that protect bacterial DNA against cognate restriction, SAM also serves as a co-factor for nucleases such as the type I restriction enzyme EcoKI, which is unable to restrict DNA in the absence of SAM. Finally, on a completely different tack, SAM can bind to certain RNA structures called riboswitches that control transcription or translation. In this way, expression of multiple genes can be regulated in a SAM-dependent manner, an unexpected finding that opens up new avenues into gene control. This minireview discusses some of these diverse and amazing roles of this small metabolite.