Glucose-induced insulin secretion [GSIS] from the pancreatic islet β cell involves the generation of second messenger molecules, including adenine nucleotides [e.g., ATP], guanine nucleotides [e.g., GTP], cAMP as well as hydrolytic products of phospholipases [e.g., diacyl glycerol and inositol phosphates]. Some of these second messengers, in turn, play essential roles in the modulation of post-translational modification [e.g., carboxyl methylation] of key regulatory proteins [e.g., G-proteins, nuclear lamins, protein phosphatases etc]. In addition, modification of specific lipids [e.g., methylation of phosphatidyl-ethanolamine to phosphatidylcholine] also represents one of the key signaling steps involved in the cascade of events leading to GSIS. Published evidence clearly suggest that lipid or protein methylation steps are catalyzed by distinct methyl transferases, which utilize S-adenosyl methionine [SAM] as the methyl donor. In this review, I will briefly discuss potential regulatory roles for protein and lipid methylation reactions in GSIS from the pancreatic β cell, specifically those data accrued through the use of pharmacological inhibitors. Potential alterations in the methylation status of some of these proteins in isolated β cells exposed to cytokines [e.g., IL-1β] are also discussed. While the existing data provide a compelling reason to support the view point that these signaling steps play key roles in the stimulus-secretion coupling of the islet β cell, further research in this area is needed to develop a more specific pharmacological agents which can selectively inhibit these signaling pathways.