With over 27,814 confirmed cases and 11 deaths (3 outside Africa) spread across the globe, the monkeypox virus is having a good run outside its historically endemic regions. A rare zoonotic disease caused by a member of the orthopoxvirus genus, similar to the causative agent of the previously eradicated smallpox disease but with milder symptoms, has transitioned to be a pathogen of public health emergency of international concern. The waning population-wide immunity provided by the smallpox vaccination, global connectedness, climate change, civil conflicts, and poverty are the likely factors contributing to the global spread. Despite 52 years having passed since it was first discovered in humans, there are gaps in knowledge regarding the ecology of the virus in the wild, host reservoirs, and definitive transmission modes; this is probably due to neglect from both regional and global authorities. The unusual prevalence of human monkeypox in men having sex with men (MSM), gay and bisexual, has generated a renewed concern regarding the possible evolution of the virus regarding sustained human-human transmission. This review highlights the epidemiology, host reservoir, transmission, diagnosis, clinical presentation, and management and prevention of human monkeypox, with further emphasis on the factors responsible for the global spread, the burden, and the neglect of the virus. In the absence of definitive therapy, a strong public health policy will help in curtailing the virus while we close the knowledge gaps that will help us eradicate and prepare for such zoonosis outbreaks.