A comprehensive review of monkeypox virus and mpox characteristics Monkeypox virus (MPXV) is the causative agent of monkeypox (mpox), a zoonotic disease. MPXV is endemic in the forested regions of West and Central Africa, but has recently spread globally, causing outbreaks in non-endemic countries. This review summarizes the characteristics of the virus, including its ecology, genomics, infection biology, and evolution. Phylogenomic molecular clock analysis suggests that the B.1 lineage responsible for the 2022 mpox outbreaks has been circulating since 2016. The review examines host-virus interactions that modulate virus infection biology, signal transduction, pathogenesis, and host immune responses. It highlights the changing pathophysiology and epidemiology of MPXV and summarizes recent advances in the prevention and treatment of mpox. The review also identifies knowledge gaps regarding the virus and disease, suggests future research directions, and proposes a One Health approach as an effective strategy to prevent current and future mpox epidemics. MPXV is a double-stranded DNA virus belonging to the Orthopoxvirus genus within the Poxviridae family. It is divided into Clade I and Clade II, with Clade II further subclassified into Clade IIa and IIb. MPXV has been reported in several countries and is endemic in Benin, Cameroon, the Central African Republic, the Democratic Republic of the Congo, Gabon, Ivory Coast, Liberia, Nigeria, the Republic of the Congo, Sierra Leone, and South Sudan. The first mpox outbreak in a non-endemic country was reported in 2003 in the USA linked to importation of rodents from Ghana. By the end of the outbreak, 47 people had been infected. Between 2018 to 2021, 11 travel-related mpox cases were recorded in the UK, Singapore, Israel, and the USA. Between 2019 and 2021, seven mpox outbreaks occurred outside Africa in Singapore, the UK and the USA. All travel-related cases originated in Nigeria, with high-throughput sequencing confirming it as Clade II. The current global mpox outbreak started in May 2022 and was declared a public health emergency of international concern on July 23, 2022. As of August 02, 2023, there were a total of 88,600 laboratory-confirmed cases and 152 deaths (case-fatality rate, 0.17%) across 113 countries, including 106 countries that have not historically reported mpox. The Americas recorded the highest number of cases during the 2022 mpox outbreak, with the USA (n = 29,513) and Brazil (A comprehensive review of monkeypox virus and mpox characteristics Monkeypox virus (MPXV) is the causative agent of monkeypox (mpox), a zoonotic disease. MPXV is endemic in the forested regions of West and Central Africa, but has recently spread globally, causing outbreaks in non-endemic countries. This review summarizes the characteristics of the virus, including its ecology, genomics, infection biology, and evolution. Phylogenomic molecular clock analysis suggests that the B.1 lineage responsible for the 2022 mpox outbreaks has been circulating since 2016. The review examines host-virus interactions that modulate virus infection biology, signal transduction, pathogenesis, and host immune responses. It highlights the changing pathophysiology and epidemiology of MPXV and summarizes recent advances in the prevention and treatment of mpox. The review also identifies knowledge gaps regarding the virus and disease, suggests future research directions, and proposes a One Health approach as an effective strategy to prevent current and future mpox epidemics. MPXV is a double-stranded DNA virus belonging to the Orthopoxvirus genus within the Poxviridae family. It is divided into Clade I and Clade II, with Clade II further subclassified into Clade IIa and IIb. MPXV has been reported in several countries and is endemic in Benin, Cameroon, the Central African Republic, the Democratic Republic of the Congo, Gabon, Ivory Coast, Liberia, Nigeria, the Republic of the Congo, Sierra Leone, and South Sudan. The first mpox outbreak in a non-endemic country was reported in 2003 in the USA linked to importation of rodents from Ghana. By the end of the outbreak, 47 people had been infected. Between 2018 to 2021, 11 travel-related mpox cases were recorded in the UK, Singapore, Israel, and the USA. Between 2019 and 2021, seven mpox outbreaks occurred outside Africa in Singapore, the UK and the USA. All travel-related cases originated in Nigeria, with high-throughput sequencing confirming it as Clade II. The current global mpox outbreak started in May 2022 and was declared a public health emergency of international concern on July 23, 2022. As of August 02, 2023, there were a total of 88,600 laboratory-confirmed cases and 152 deaths (case-fatality rate, 0.17%) across 113 countries, including 106 countries that have not historically reported mpox. The Americas recorded the highest number of cases during the 2022 mpox outbreak, with the USA (n = 29,513) and Brazil (