This article examines the biosecurity and biodefense implications resulting from the recent creation of horsepox virus, a noncirculating (extinct) species of orthopoxvirus. Here we examine the technical aspects of the horsepox virus synthesis and conclude that orthopox synthesis experiments currently remain technically challenging-and will continue to be so, even once this work is published in the scientific literature. This limits potential misuse by some types of nefarious actors. We also examine the implications of one stated purpose for the recreation of horsepox virus: the development of a smallpox vaccine. If the development is successful, it could take advantage of US government incentives for the priority FDA review of medical countermeasures (MCMs) against biosecurity threats. However, if this case leads to the determination that this incentive is counterproductive for security, the newly created priority review voucher program should be more clearly defined or limited based on need. Limiting the program could have costs that require further consideration, however, as general incentives for biodefense medical countermeasure development are required for MCMs to be available. Finally, while the recreation of horsepox virus was not technically trivial, nor was it cell-free, this experiment was a de facto demonstration of already-assumed scientific capabilities. The ability to recreate horsepox, or smallpox, will remain no matter what policy controls are put into place. It will be impossible to close off all avenues for nefarious misuse of gene synthesis, or misuse of biological materials more broadly. As a result, we advocate for the implementation of policy, regulations, and guidance that will make illicit recreation harder, more burdensome, more detectable, and, thus, more preventable without having sweeping negative consequences for the research enterprise. As part of our biosecurity efforts, we must also encourage and enable scientists to participate actively and to do all they can to safeguard their technical fields from irresponsible or illicit actions.