Transfer RNAs (tRNAs) are adapter molecules needed to translate genetic information into a peptide sequence. At the ribosome, the anticodon of each tRNA reads the corresponding codon of the messenger RNA. This anticodon– codon interaction allows the ribosome_s large subunit to catalyze amide-bond formation between the cognate amino acids present at the 3’ terminus of aminoacyl-tRNAs and the growing peptide chain. The tRNA adapters required for this process display a surprisingly large chemical diversity. Aside from the four canonical nucleosides A, C,G, and U, more than 100 modified nucleosides are key constituents. The most diverse and complex chemical structures are found in the anticodon stem-loop either in the anticodon at the wobble position or directly adjacent to the 3’ position of the anticodon, suggesting that here the chemical complexity is necessary to establish translational fidelity. The ribosome seems to need the modified anticodon region to better distinguish correctly base-paired tRNA from mispaired interactions in order to prohibit, for example, codon-slippage processes that would lead to frameshifts.