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ABSTRACT Mpox disease, caused by the monkeypox virus (MPXV), was recently classified as a public health emergency of international concern due to its high lethality and pandemic potential. MPXV is a zoonotic disease that emerged and is primarily spread by small rodents. Historically, it was considered mainly zoonotic and not likely to sustain human-to-human transmission. However, the worldwide outbreak of Clade IIb MPXV from 2020 to 2022 and ongoing Clade I MPXV epidemics in the Democratic Republic of the Congo and surrounding areas are a warning that human-adapted MPXVs will continually arise. Understanding the viral genetic determinants of host range, pathogenesis, and immune evasion is imperative for developing control strategies and predicting the future of Mpox. Here, we delve into the MPXV genome to detail genes involved in host immune evasion strategies for this zoonotic rodent-borne and human-circulating virus. We compare MPXV gene content to related Orthopoxviruses, which have narrow host ranges, to identify potential genes involved in species-specific pathogenesis and host tropism. In addition, we cover the key virulence factor differences that distinguish the MPXV clade lineages. Finally, we dissect how genomic reduction of Orthopoxviruses, through various molecular mechanisms, is contributing to the generation of novel MPXV lineages with increased human adaptation. This review aims to highlight gene content that defines the MPXV species, MPXV clades, and novel MPXV lineages that have culminated in this virus being elevated to a public health emergency of national concern.