Diabetes, a disorder of glucose homeostasis, has risen to near epidemic proportions world-wide and may be the single most important risk factor for cardiovascular, kidney, and eye disease. Dysfunction and destruction of islet beta cells, caused in part by the systemic or local release of pro-inflammatory cytokines, underlies all forms of diabetes. A major effort in diabetes research in recent years has been to identify new factors or pathways that can be therapeutically targeted to reduce cytokine action on the beta cell. Recent studies have suggested that an ancient and poorly understood protein, eIF5A, may be critical to cytokine release and signaling. Interestingly, eIF5A is the only protein to contain the unique amino acid hypusine, which is a polyamine-derived modification of amino acid lysine residue. This modification is catalyzed by the sequential actions of the inhibitable enzymes deoxyhypusine synthase and deoxyhypusine hydroxylase. Because the hypusine modification is absolutely required for eIF5A action in cytokine signaling, we propose that this modification could serve as a new drug target for islet beta cell protection in the setting of diabetic inflammation.