In May 2022, the world witnessed the re-emergence of the zoonotic disease monkeypox. While this was not the first epidemic of this disease, what differentiated the outbreak was the rapid global spread and increase of cases, which led the WHO to declare monkeypox a global health emergency. Although the disease spreads mainly through inadequately cooked meat of various rodent species, this virus also shows droplet, respiratory, sexual, and even vertical transmission. Monkeypox further multiplies in lymphoproliferative organs and presents with a classical smallpox-like rash, fever, headache, and muscle aches. Diagnosis is confirmed with a polymerase-chain-reaction test and is managed largely supportively with possible usage of some antivirals and immunoglobulins. Moreover, some pre-exposure and postexposure prophylactic vaccines have been developed. This paper aims to conduct an in-depth review of the historical epidemics, transmission, pathophysiology, clinical presentation, and management of the monkeypox disease.