Monkeypox (Mpox), caused by monkeypox virus (MPXV), has shifted from an endemic zoonosis in Central and West Africa to a pathogen of global public health significance. Two World Health Organization (WHO) Public Health Emergencies of International Concern were declared and subsequently lifted. Clade Ib has continued to emerge in the Democratic Republic of the Congo and neighboring countries, recombinant MPXV strains have been detected, and inequities in access to diagnostics, vaccines, and therapeutics persist. These factors need critical synthesis to inform clinical practice and public health preparedness. This paper reviewed MEDLINE, Embase, WHO situation reports, the United States Centers for Disease Control and Prevention, and Prevention surveillance bulletins, prioritizing peer-reviewed literature and official reports, with preprints identified where cited. MPXV comprises two major clades with distinct epidemiological, clinical, and virological profiles. Clade Ib shows apolipoprotein B mRNA editing enzyme catalytic subunit 3 consistent mutational signatures indicating sustained human adaptation, and has driven a large ongoing outbreak in Central and East Africa. Clade IIb drove the 2022 global outbreak, predominantly through sexual contact among men who have sex with men. Diagnosis relies on polymerase chain reaction of lesion specimens, with whole genome sequencing needed for subclade and recombinant characterization. Tecovirimat has shown no significant clinical benefit in randomized trials for clade I disease, leaving treatment guidance unresolved. JYNNEOS offers approximately 82% pre-exposure effectiveness against clade IIb, though direct clade Ib effectiveness data remain limited, and equitable access to countermeasures in high-burden African settings remains critically inadequate. Priorities include strengthened genomic surveillance in Africa, expanded access to JYNNEOS, and urgent clade Ib-specific effectiveness data.