This comprehensive review examines the characteristics of the monkeypox virus (MPXV) and mpox, including its ecology, genomics, infection biology, and evolution. MPXV, a double-stranded DNA virus belonging to the *Orthopoxvirus* genus, has been endemic in West and Central Africa but has recently spread globally, causing outbreaks in multiple non-endemic countries. The review estimates that the B.1 lineage responsible for the 2022 mpox outbreaks has been circulating since 2016. It explores host-virus interactions, signal transduction, pathogenesis, and host immune responses. The changing pathophysiology and epidemiology of MPXV are highlighted, along with recent advances in prevention and treatment. The review identifies knowledge gaps and suggests future research directions, proposing a one-health approach to prevent current and future mpox epidemics. The global mpox outbreak timeline, from 1970 to 2023, is presented, showing a significant increase in cases outside endemic regions since 2017. The review also discusses the ecology, host range, tissue and cell tropism of MPXV, and its spillover to humans. Genomic analysis reveals differences in gene content and phylogenetic relationships between Clade I and Clade II isolates. The review examines the virus's morphogenesis, pathogenesis, and strategies to manipulate signaling pathways and evade host immune responses. Finally, it provides an epidemiological overview, including demographic characteristics and case fatality rates, highlighting the shift in age and gender distribution during the 2022 outbreak.This comprehensive review examines the characteristics of the monkeypox virus (MPXV) and mpox, including its ecology, genomics, infection biology, and evolution. MPXV, a double-stranded DNA virus belonging to the *Orthopoxvirus* genus, has been endemic in West and Central Africa but has recently spread globally, causing outbreaks in multiple non-endemic countries. The review estimates that the B.1 lineage responsible for the 2022 mpox outbreaks has been circulating since 2016. It explores host-virus interactions, signal transduction, pathogenesis, and host immune responses. The changing pathophysiology and epidemiology of MPXV are highlighted, along with recent advances in prevention and treatment. The review identifies knowledge gaps and suggests future research directions, proposing a one-health approach to prevent current and future mpox epidemics. The global mpox outbreak timeline, from 1970 to 2023, is presented, showing a significant increase in cases outside endemic regions since 2017. The review also discusses the ecology, host range, tissue and cell tropism of MPXV, and its spillover to humans. Genomic analysis reveals differences in gene content and phylogenetic relationships between Clade I and Clade II isolates. The review examines the virus's morphogenesis, pathogenesis, and strategies to manipulate signaling pathways and evade host immune responses. Finally, it provides an epidemiological overview, including demographic characteristics and case fatality rates, highlighting the shift in age and gender distribution during the 2022 outbreak.