Genomic DNA is composed of four standard nucleotides, each with a different nucleobase: adenine (A), thymine (T), cytosine (C), and guanine (G). These nucleobases form the genetic alphabet, ATCG, which is conserved across all domains of life. However, in 1977, the DNA virus cyanophage S-2L was discovered with all instances of A substituted with 2-aminoadenine (Z) throughout its genome (1, 2), forming the genetic alphabet ZTCG. Studies revealed interesting properties of Z-substituted DNA (dZ-DNA) (3–6), but little of Z synthesis was understood. On pages 516 and 512 of this issue, Sleiman et al. (7) and Zhou et al. (8), respectively, characterize viral Z biosynthesis. On page 520, Pezo et al. (9) identify a Z-specific DNA polymerase that is responsible for assembling dZ-DNA from nucleotides. All three studies identify additional “Z-genomes” in diverse bacteriophages (viruses that infect bacteria), which may have offered evolutionary advantages alongside standard ATCG DNA since life began.