Programmed S1 ribosomal frameshifting (S1PRF) is an mRNA recoding event commonly utilized by viruses and bacteria to increase the information content of their genomes. Recent results have implicated S1PRF in quality control of mRNA and DNA stability in eukaryotes. Biophysical experiments demonstrated that the ribosome changes the reading frame while attempting to move over a slippery sequence of the mRNA -when a roadblock formed by a folded downstream segment in the mRNA stalls the ribosome in a metastable conformational state. The efficiency of S1PRF is modulated not only by cis-regulatory elements in the mRNA but also by transacting factors such as proteins, miRNAs, and antibiotics. These recent results suggest a molecular mechanism and new important cellular roles for S1PRF.Accurate decoding versus programmed recoding Ribosomes (see Glossary) are cellular factories that produce proteins in all cells using the nucleotide sequence of mRNAs as a blueprint. Nucleotide triplets of an mRNAthe codons -are translated into an amino acid sequence of a protein. The selection of the translation start and the reading frame on an mRNA is tightly controlled during the initiation phase of protein synthesis. The subsequent elongation phase entails repeated cycles of codon decoding by aminoacyl-tRNA, peptide bond formation, and tRNAmRNA translocation. Elongation cycles continue until the ribosome reaches a stop codon, on which translation is terminated. It is intuitively clear that translation of an mRNA sequence into a protein must be colinear and highly accurate. Errors can lead to the formation of toxic or misfolded proteins, increase the energetic cost of translation, and cause additional load on the cellular clean-up and quality-control machineries [1]. To avoid this burden, cells have evolved sophisticated control mechanisms that ensure the fidelity of decoding and reading frame maintenance. However, in special cases, the ribosomes, guided by signals encoded in the mRNA, abandon the principle of mRNAprotein colinearity and read the message in an alternative way, which results in mRNA recoding (Box 1) [2][3][4].Programmed frameshifting is a recoding event that can occur in the + or À direction relative to the normal 0-frame mRNA translation by shifting the ribosome by one or two nucleotides, thereby producing two (or even three) different proteins from one mRNA. In contrast to spontaneous frameshifting, which is infrequent, the efficiency of programmed frameshifting may be as high as 80%, although in many cases it is only a few percent [5]. Programmed frameshifting increases the coding potential of the genome and is often used to expand the variability of cellular proteomes, adapt to changing environments, or ensure a defined stoichiometry of protein products. The mechanisms of +1 and À1 frameshifting appear to be different, and particularly the mechanism of À1 programmed ribosome frameshifting (À1PRF), its abundance, and physiological significance have remained unclear for a long time. The advances of biophysical techniqu...