Abstract Orthopoxviruses are complex, large-genome DNA viruses that have repeatedly confounded expectations in terms of the clinical illness they cause and their patterns of spread. Monkeypox virus (MPXV) was originally characterized during outbreaks among captive primates in the late 1950's. Human disease (mpox) has been observed since the 1970’s and inter-human spread has largely been associated with non-sexual, close physical contact in endemic areas of west and central Africa. In May 2022, a focus of Clade IIb MPXV transmission was detected, spreading largely by sexual contact through international networks of gay, bisexual, and other men who have sex with men. Despite decades of preparedness for the potential biothreat risk posed by smallpox, the outbreak grew in both size and geographic scope, testing the strength of smallpox preparedness tools and public health science alike. In this article we consider what was known about mpox prior to the 2022 outbreak, what we have learned about mpox and Clade IIb virus during the outbreak, and what outbreak response actions and continued research are needed to ensure the global public health community is equipped to detect and halt the further spread of this disease threat. We focus on how epidemiologic characterization and investigation together with laboratory studies have advanced our understanding of the transmission and pathogenesis of mpox, and describe what work remains to be done to optimize diagnostics, therapeutics, and vaccines. Persistent health inequities challenge our capacity to fully eliminate circulation of the 2022 outbreak strain of MPXV currently in the United States.