Monkeypox (mpox) is a new zoonotic disease identified as the most significant Orthopoxvirus (OPV) infection in humans since the elimination of smallpox and the subsequent discontinuation of smallpox immunization. Monkeypox has been regarded as a manageable yet overlooked disease in Africa for several decades. However, since its dissemination outside Africa and its evolution changing its main mode of zoonotic transmission and causing subsequent worldwide outbreaks, it has raised international concerns among the WHO and many health authorities. Phylogenetic data raise concerns regarding the potentially enhanced adaptation of the existing virus strains to humans. Although the natural viral reservoir remains unidentified, monkeypox virus (MPXV) possesses a wide host range, enabling it to sustain a wildlife reservoir while intermittently inducing disease in humans, hence hindering worldwide eradication efforts by vaccination in humans.