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Mpox was first identified against the backdrop of the smallpox eradication campaign. Monkeypox virus (MPXV), the causative agent of mpox, has been maintained in animal reservoirs in the forested regions of West and Central Africa as 2 distinct clades; clade I has historically caused more severe infection in Central Africa than clade II, historically found in West Africa. However, rapid reemergence and spread of both MPXV clades through novel routes of transmission have challenged the known characteristics of mpox. We summarize mpox demographic distribution, clinical severity, and case-fatality rates attributed to genetically distinct MPXV subclades and focus on MPXV clade Ib, the more recently identified subclade. Broad worldwide assistance will be necessary to halt the spread of both MPXV clades within mpox endemic and nonendemic regions to prevent future outbreaks.