Cordyceps s.l. (sensu lato) species have been used as herbal medicines; one of their main constituents is cordycepin. As genome sequencing techniques have become more cost-effective and more popular, more entomogenous fungal genomes have been sequenced and published. Here, we constructed a phylogenetic tree based on 18S rRNA sequences from Cordyceps species and analyzed the copy number of the key enzymes involved in biosynthesis of cordycepin from related fungal genomes that have been published. The sequences of the 18S rRNA gene were examined, and seven single nucleotides were found that could represent the evolutionary history of Cordyceps s.l. and which perfectly fit the phylogenetic tree. Their evolution was influenced mainly by host factors, rather than geographical location. The Cordyceps s.l. species that are used as herbal medicines are closely related in the phylogenetic tree. The major species for Chinese pharmaceutical markets, such as C. militaris and C. sinensis, have higher copy numbers of 5'-nucleotidase and adenylate kinase, and ribonucleotide reductases (RNRs), respectively. Moreover, absence of an RNR inhibitor may cause cordycepin accumulation. Presence of an RNR inhibitor may lead to lower cordycepin levels in fungal species in which no medicinal applications have been described. Cordycepin is not only an important secondary metabolite that is used as an herbal medicine, but it also has significance for understanding the evolution of these entomogenous species.