LepA [EF4 (elongation factor 4)] is a highly conserved protein found in nearly all known genomes. EF4 triggers back-translocation of the elongating ribosome, causing the translation machinery to move one codon backwards along the mRNA. Knockout of the corresponding gene in various bacteria results in different phenotypes; however, the physiological function of the factor in vivo is unclear. Although functional research on Guf1 (GTPase of unknown function 1), the eukaryotic homologue of EF4, showed that it plays a critical role under suboptimal translation conditions in vivo, its detailed mechanism has yet to be identified. In the present review we briefly cover recent advances in our understanding of EF4, including in vitro structural and biochemical studies, and research on its physiological role in vivo. Lastly, we present a hypothesis for back-translocation and discuss the directions future EF4 research should focus on.