During protein synthesis, codons in mRNA are translated sequentially in frame on the ribosome following strict decoding rules. This process is usually very accurate. However, in some cases, recoding events occur at selected codons, leading to a high frequency of frameshifting or stop codon readthrough. The factors influencing these noncanonical decoding events are very diverse; among them are the codon usage and context, the presence of a stable mRNA secondary structure downstream of the decoding sites and the type and relative abundance of normally modified tRNA. Here, we discuss the role of certain modified nucleotides of tRNAs in a few cases of frameshifting and readthrough that occur in Bacteria and Eukarya. While in some cases the effect of a given modified nucleotide in a tRNA is to increase accuracy of the recoding process, in a few other cases the reverse has been observed. This review illustrates the power of using well characterized recoding systems, coupled with specific defects of RNA modification enzymes to assay for translational fidelity under in vivo conditions.