The 2022 mpox epidemic was driven by underdetected dispersal and extensive local transmission, particularly among high-risk groups. Phylodynamic models revealed rapid spread between five global regions, with extensive underdetected dissemination promoting rapid local transmission. Later introductions played a minor role in prolonging regional epidemics. In North America, the epidemic declined before 10% of high-risk individuals had vaccine-induced immunity. The study combined genomic, mobility, and epidemiological data to show that local behavioral changes were more effective in curbing transmission than travel restrictions or vaccination campaigns. Genomic epidemiology is crucial for understanding global transmission dynamics and guiding outbreak control. The epidemic was characterized by undetected spread prior to initial case discovery, with presymptomatic transmission contributing to its spread. The WHO declared mpox a public health emergency, prompting investigations into transmission and control measures. Vaccination efforts were delayed in high-risk areas, and the extent of international travel's role in the epidemic remains unclear. Genomic data showed significant transmission heterogeneity, with a large proportion of cases resulting from early introductions. The study highlights the importance of routine specimen screening and integrating genomic and epidemiological data for early outbreak control. Vaccination campaigns had limited impact on reducing the epidemic in North America, with local transmission declining before significant immunity was achieved. Behavioral changes within high-risk groups were more effective in curbing transmission than vaccination. The study underscores the need for prompt public health responses to maximize the effectiveness of vaccination campaigns. The findings emphasize the importance of early detection and behavioral modification in controlling emerging infectious diseases.The 2022 mpox epidemic was driven by underdetected dispersal and extensive local transmission, particularly among high-risk groups. Phylodynamic models revealed rapid spread between five global regions, with extensive underdetected dissemination promoting rapid local transmission. Later introductions played a minor role in prolonging regional epidemics. In North America, the epidemic declined before 10% of high-risk individuals had vaccine-induced immunity. The study combined genomic, mobility, and epidemiological data to show that local behavioral changes were more effective in curbing transmission than travel restrictions or vaccination campaigns. Genomic epidemiology is crucial for understanding global transmission dynamics and guiding outbreak control. The epidemic was characterized by undetected spread prior to initial case discovery, with presymptomatic transmission contributing to its spread. The WHO declared mpox a public health emergency, prompting investigations into transmission and control measures. Vaccination efforts were delayed in high-risk areas, and the extent of international travel's role in the epidemic remains unclear. Genomic data showed significant transmission heterogeneity, with a large proportion of cases resulting from early introductions. The study highlights the importance of routine specimen screening and integrating genomic and epidemiological data for early outbreak control. Vaccination campaigns had limited impact on reducing the epidemic in North America, with local transmission declining before significant immunity was achieved. Behavioral changes within high-risk groups were more effective in curbing transmission than vaccination. The study underscores the need for prompt public health responses to maximize the effectiveness of vaccination campaigns. The findings emphasize the importance of early detection and behavioral modification in controlling emerging infectious diseases.