Diphthamide is a highly conserved modification of archaeal and eukaryal translation elongation factor 2 (EF2) and yet why cells need EF2 to contain diphthamide is unclear. In yeast, the first steps of diphthamide synthesis and the genes (DPH1-DPH5) required to form the intermediate diphthine are well-documented. However, the last step, amidadation of diphthine to diphthamide, had largely been ill-defined. Remarkably, through mining genome-wide synthetic gene array (SGA) and chemical genomics databases, recent studies by Uthman et al. [PLoS Genetics (2013) 9, e1003334] and Su et al. [Proc. Natl. Acad. Sci. USA (2012) 109, 19983-19987] have identified two more diphthamide players, DPH6 and DPH7. Consistent with roles in the amidation step, dph6 and dph7 deletion strains fail to complete diphthamide synthesis and accumulate diphthine-modified EF2. In contrast to Dph6, the catalytically relevant amidase, Dph7 appears to be regulatory. As shown by Uthman et al., it promotes dissociation of diphthine synthase (Dph5) from EF2, allowing diphthine amidation by Dph6 to occur and thereby coupling diphthine synthesis to the terminal step in the pathway. Remarkably, the study by Uthman et al. suggests that Dph5 has a novel role as an EF2 inhibitor that affects cell growth when diphthamide synthesis is blocked or incomplete and, importantly, shows that diphthamide promotes the accuracy of EF2 performance during translation.