Abstract There is a growing appreciation that synonymous codon usage, although historically regarded as phenotypically silent, can instead alter a wide range of mechanisms related to functional protein production, a term we use here to describe the net effect of transcription (mRNA synthesis), mRNA half‐life, translation (protein synthesis) and the probability of a protein folding correctly to its active, functional structure. In particular, recent discoveries have highlighted the important role that sub‐optimal codons can play in modifying co‐translational protein folding. These results have drawn increased attention to the patterns of synonymous codon usage within coding sequences, particularly in light of the discovery that these patterns can be conserved across evolution for homologous proteins. Because synonymous codon usage differs between organisms, for heterologous gene expression it can be desirable to make synonymous codon substitutions to match the codon usage pattern from the original organism in the heterologous expression host. Here we present CHARMING (for Codon HARMonizING), a robust and versatile algorithm to design mRNA sequences for heterologous gene expression and other related codon harmonization tasks. CHARMING can be run as a downloadable Python script or via a web portal at http://www.codons.org .