Abstract: Cellular efficiency in protein translation is an important fitness determinant in many organisms. It is commonly assumed that different synonymous codons are translated with different speeds and that translational efficiency is maximized by the exclusive use of rapidly translated codons. Unexpectedly, we observe similar translational speeds among synonymous codons in yeast, which we hypothesize to have resulted from codon usage in proportion to cognate tRNA concentrations, the optimal strategy to maximize translational efficiency under tRNA shortage. This codon-tRNA balance is indeed observed from all eukaryotic genomes examined, and its impact on translational efficiency is further validated in a yeast molecular experiment. Our study reveals a previously unsuspected mechanism by which unequal codon usage enhances translational efficiency, and offers new strategies to improve synthetic biology.