BACKGROUND The 2022 mpox outbreak drew global attention to this neglected pathogen. While most of the world was taken by surprise, some countries have seen this pathogen emerge and become endemic several decades prior to this epidemic. OBJECTIVES This narrative review provides an overview of mpox epidemiology since its discovery through the 2022 global outbreak. SOURCES We searched PubMed for relevant literature about mpox epidemiology and transmission through 28 February 2023. CONTENT The emergence of human mpox is intertwined with the eradication of smallpox and cessation of the global smallpox vaccination campaign. The first human clade I and II MPXV infections were reported as zoonoses in Central and West Africa, respectively, around 1970 with sporadic infections reported throughout the rest of the decade. Over the next five decades, Clade I MPXV was more common, and caused outbreaks of increasing size and frequency, mainly in the Democratic Republic of the Congo. Clade II MPXV was rarely observed, until its reemergence and ongoing transmission in Nigeria, since 2017. Both clades showed a shift from zoonotic to human-to-human transmission, with potential transmission through sexual contact being observed in Nigeria. In 2022, clade II MPXV caused a large human outbreak which to-date has caused over 86,000 cases in 110 countries, with strong evidence of transmission during sexual contact. By February 2023, the global epidemic has waned in most countries, but endemic regions continue to suffer from mpox. IMPLICATIONS The changing epidemiology of mpox demonstrates how a neglected zoonosis turned into a global health threat within a few decades. Thus, mpox pathophysiology and transmission dynamics need to be further investigated, and preventive and therapeutic interventions need to be evaluated. Outbreak response systems need to be strengthened and sustained in endemic regions to reduce the global threat of mpox.