Codon usage bias is a fundamental aspect of the genetic code. For many years synonymous mutations to a coding sequence were considered to be functionally “silent.” We now appreciate that is not the case and that synonymous codon choice can have drastic implications for gene expression and protein production. A major debate in the field remains whether codon usage bias is evolutionarily selected for to drive efficient translation in a tissue-specific manner. Here we perform an organism wide screen in Drosophila using codon modified reporters to reveal tissue-specific responses to codon usage bias. We uncover a strict limit on rare codon usage for protein expression, and this limit coincides with the rareness limit of endogenous genes in Drosophila. We find that rare codon usage near the edge of this limit is sufficient to impart tissuespecific gene expression, notably in the testis and brain. We define a new codon usage metric, the tissue-apparent Codon Adaptation Index (taCAI) to reveal a conserved enrichment in rare codons in endogenous testis genes of both flies and humans. We further demonstrate that rare codons in the evolutionarily young gene, RpL10Aa, are required for female fertility.