ABSTRACT:  Fidelity of mRNA translation is regulated by the accuracy of aminoacyl-tRNA synthetases, the enzymes that couple each proteinogenic amino acid with the cognate tRNA. Typically, the selectivity of the aminoacyl-tRNA synthetases towards the tRNA substrates is quite stringent and depends on the recognition of the anticodon loop and sequence among other recognition elements. Here, I will describe how two distinct tRNA-dependent enzymes, a yeast mitochondrial ThrRS (MST1) and human selenocysteine synthase (SepSecS), employ different strategies for tRNA recognition, which are in turn essential for  gene translation. In the case MST1, the enzyme binds and acts on two isoacceptor tRNAs that have completely different anticodon sequences, whereas SepSecS evolved to bind specifically an unusual selenocysteine tRNA