 The eradication of smallpox was achieved through a global vaccination program initiated by the World Health Organization, who this program resulted in decreasing herd immunity against smallpox, leading to a global health crisis. Smallpox vaccinations induce both humoral and cellular immune responses, providing protection from smallpox and other related zoonotic orthopox viruses. Recent reports of increasing numbers of monkeypox cases highlight the need for further research on these viruses and their potential transmission routes. Animal and cell line models have been used to study host antiviral defense mechanisms and orthopox virus evasion strategies. These studies provide insights into how to develop more effective vaccines and treatments for pox virus infections. This article was authored by Maugorzata Jorinska, Lydia Sulte-Debrowska, Justina Struzik, and others.