The DNAs of bacterial viruses are known to contain diverse, chemically complex modifications to thymidine to protect the viral DNA from the endonuclease-based defenses of the bacterial hosts, but their biosynthetic processes are enigmatic. Up to half of thymidines in the Pseudomonas phage M6, the Salmonella phage ViI, and others, contain exotic chemical moieties synthesized via the post-replicative modification of 5-hydroxymethyluridine (5-hmdU) on the genomic DNA. The gene candidates involved in the biosynthesis process were predicted through comparative genomic analysis of the thymidine hypermodified phages. We have determined that these thymidine hypermodifications are derived from free amino acids enzymatically installed on 5-hmdU. Various enzyme classes, such as radical SAM isomerases, PLP-dependent decarboxylases, flavin-dependent lyases, and acetyltransferases, further sculpt these appended amino acids. The combinatorial permutations of thymidine hypermodification genes found in viral metagenomes from geographically widespread sources suggest an untapped reservoir of chemical diversity in DNA hypermodifications.