Negative supercoiling of DNA generated during transcription stabilizes its left-handed Z-DNA conformation. Proteins that bind selectively to Z-DNA also stabilize that conformation. Two human protein domains have been isolated that bind to Z-DNA with conformational specificity, as shown by crystal structures of the protein - Z-DNA complexes. The two proteins differ considerably in sequence but their Z-DNA interactions are similar. A third member of this class is the E3L protein of pox viruses. The lethality of vaccinia virus for a mouse depends upon the presence of the E3L viral gene product. When the E3L domain of vaccinia virus is removed and replaced with either of the two Z-DNA binding proteins whose crystal structure is known, the virus retains lethality. However, when mutations are made in the Z-DNA binding proteins that weaken binding to Z-DNA, a lessening of virulence is seen. When a protein that does not bind Z-DNA is incorporated into the E3L position, the virus is not lethal. However, if that protein is mutated so that it does bind Z-DNA, the virus becomes lethal. Z-DNA binding by the E3L protein is thus an essential component of virulence in vaccinia viruses. It is likely that a small molecule can be found that would attach to the Z-DNA binding site of the protein and thereby prevent virulence of vaccinia virus in mice. Since variola, the agent of smallpox has a virtually identical E3L molecule, it is likely that this small molecule will also prevent the pathology of smallpox.