A systematic review of peer-reviewed and grey literature reveals that the epidemiology of human monkeypox has changed significantly since its first diagnosis in 1970 in the Democratic Republic of the Congo (DRC). The number of confirmed, probable, and/or possible cases has increased dramatically, with the most significant increases occurring in the DRC. The median age at presentation has increased from 4 years in the 1970s to 21 years in 2010–2019. The case fatality rate (CFR) was 10.6% for the Central African clade and 3.6% for the West African clade. Cases outside Africa have occasionally resulted in outbreaks, particularly following travel or exposure to infected animals. The review highlights an escalation of monkeypox cases, especially in the DRC, a spread to other countries, and a growing median age from young children to young adults. These findings may be related to the cessation of smallpox vaccination, which provided some cross-protection against monkeypox, leading to increased human-to-human transmission. The appearance of outbreaks beyond Africa highlights the global relevance of the disease. Increased surveillance and detection of monkeypox cases are essential tools for understanding the continuously changing epidemiology of this resurging disease. The review also found that the majority of monkeypox cases occurred in unvaccinated individuals, and that human-to-human transmission is a concern. The study concludes that the waning population immunity associated with the discontinuation of smallpox vaccination has established the landscape for the resurgence of monkeypox. The appearance of cases outside of Africa highlights the risk for geographical spread and the global relevance of the disease. The possibility for human-to-human transmission is a concern not just among household members, but also among providers of care to diseased individuals. The public health importance of monkeypox disease should not be underestimated. International support for increased surveillance and detection of monkeypox cases are essential tools for understanding the continuously changing epidemiology of this resurging disease.A systematic review of peer-reviewed and grey literature reveals that the epidemiology of human monkeypox has changed significantly since its first diagnosis in 1970 in the Democratic Republic of the Congo (DRC). The number of confirmed, probable, and/or possible cases has increased dramatically, with the most significant increases occurring in the DRC. The median age at presentation has increased from 4 years in the 1970s to 21 years in 2010–2019. The case fatality rate (CFR) was 10.6% for the Central African clade and 3.6% for the West African clade. Cases outside Africa have occasionally resulted in outbreaks, particularly following travel or exposure to infected animals. The review highlights an escalation of monkeypox cases, especially in the DRC, a spread to other countries, and a growing median age from young children to young adults. These findings may be related to the cessation of smallpox vaccination, which provided some cross-protection against monkeypox, leading to increased human-to-human transmission. The appearance of outbreaks beyond Africa highlights the global relevance of the disease. Increased surveillance and detection of monkeypox cases are essential tools for understanding the continuously changing epidemiology of this resurging disease. The review also found that the majority of monkeypox cases occurred in unvaccinated individuals, and that human-to-human transmission is a concern. The study concludes that the waning population immunity associated with the discontinuation of smallpox vaccination has established the landscape for the resurgence of monkeypox. The appearance of cases outside of Africa highlights the risk for geographical spread and the global relevance of the disease. The possibility for human-to-human transmission is a concern not just among household members, but also among providers of care to diseased individuals. The public health importance of monkeypox disease should not be underestimated. International support for increased surveillance and detection of monkeypox cases are essential tools for understanding the continuously changing epidemiology of this resurging disease.