While its mechanism and biological significance are unknown, the utility of a short mitochondrial DNA sequence as a “barcode” providing accurate species identification has revolutionized the classification of organisms. Since highest accuracy was achieved with recently diverged species, hopes were raised that barcodes would throw light on the speciation process. Indeed, a failure of a maternally donated, rapidly mutating, mitochondrial genome to coadapt its gene products with those of a paternally donated nuclear genome could result in developmental failure, thus creating (...) a post-zygotic barrier leading to reproductive isolation and sympatric branching into independent species. However, the barcode itself encodes a highly conserved, species-invariant, protein, and the discriminatory power resides in the non-amino acid specific bases of synonymous codons. It is here shown how the latter could register changes in the oligonucleotide frequencies of nuclear DNA that, when they fail to match in pairing meiotic chromosomes, could reproductively isolate the parents so launching a primary divergence into two species. It is proposed that, while not itself contributing to speciation, the barcode sequence provides an index of the nuclear DNA oligonucleotide frequencies that drive speciation. (shrink)