MPOXV is a double-stranded DNA virus (ds-DNA) that recently caused widespread infection in humans. The eradication of smallpox and subsequent decrease or near elimination of vaccination against the smallpox virus resulted in a lack of herd immunity to the smallpox viral infection which then facilitated the resurgence of MPOXV. Two different clades of virus are described belonging to Central Africa and West Africa. The clade from Central Africa is more virulent, resulting in a higher mortality. In this commentary we describe epidemiology, genetic structure, mechanism of infection, the immune response, clinical presentation, differential diagnosis, complications, laboratory diagnosis, prevention, therapeutic options, societal outlook, and prognosis.