Codon-optimization describes gene engineering approaches that use synonymous codon changes to increase protein production. It is used extensively for expressing recombinant protein drugs, gene therapy, and DNA/RNA vaccines. However, it is becoming increasingly clear that codon-optimization can affect protein conformation and function, increase the immunogenicity of recombinant protein drugs, and reduce efficacy. This presentation will analyze the mechanisms and assumptions underlying codon optimization and identify additional hazards associated with this approach, including unique hazards for gene therapy and DNA/RNA vaccine applications.