In May 2022, a new global outbreak of mpox (formerly, human monkeypox) emerged that was declared a public health emergency of international concern by the World Health Organization on July 23, 2022. With new patterns of person-to-person spread within sexual networks in nonendemic countries and several differences from the classic disease course, we performed a comprehensive review of existing literature on human monkeypox to discuss epidemiology, modes of transmission, clinical presentation and asymptomatic infection, diagnostics, therapeutics, and vaccines with the primary aim to identify important areas for future research of this new epidemic form of the disease. A comprehensive literature search was performed of all published literature to August 15, 2022. Historically, in regions of monkeypox virus endemicity, human outbreaks have occurred related to discrete zoonotic events. The animal reservoir is unknown, but the virus has been isolated from rodents. Traditionally, transmission occurred by direct or indirect contact with an infected animal. In nonendemic countries affected in the 2022 outbreak, almost exclusive person-to-person spread has been observed, and most cases are connected to sexual networks of gay, bisexual, and other men who have sex with men. After an incubation period of approximately 13 days, in traditional human cases affected persons developed a febrile prodrome preceding a rash that started on the face and body, spread centrifugally to the palms and soles and healed monomorphically over two to four weeks. However, in the 2022 outbreak, the febrile illness is often absent or occurs after the onset of the rash. The rash presents primarily in the anogenital region and face before disseminating throughout the body, with lesions displaying regional pleomorphism. There is a paucity of data for the role of antiviral agents or vaccines. The epidemiology and clinical course of mpox has changed in the 2022 epidemic from that observed with the endemic disease. There is an urgent need to establish rapid and collaborative research platforms to diagnose, treat and prevent disease and inform important public health and other strategies to stop the spread of disease.