Smallpox rickettsia is an urban zoonosis caused by Rickettsia akari. To date, R. akari is the only characterized representative of the group of spotted fevers transmitted by the gamasid mite Liponyssoides sanguineus, which is common among peridomic rodents. This disease was first described in New York in 1946, and a few years later a similar outbreak occurred in the Ukrainian SSR. Numerous serological studies and diagnostics of sporadic cases of smallpox rickettsiosis suggest its widespread occurrence on the planet; however, the current geography and incidence of smallpox rickettsiosis is unknown. Smallpox rickettsiosis is characterized by the classic clinical triad of primary affect, high fever, and atypical papulovesicular rash. Dermatological manifestations and progression of smallpox rickettsiosis may resemble other infectious and non-infectious syndromes, including sexually transmitted diseases. This review aimed to raise awareness of this unique disease by analyzing the classic and current clinical descriptions of rickettsial pox, assessing its global prevalence and new insights into its public health relevance, and the ecology and vector-vector relationship of R. akari. Analysis of the data indicates that there is only limited genetic diversity among the available R. akari isolates from previous outbreaks. Additional efforts will be required to identify specific genetic markers that allow for epidemiological surveillance, as well as accurate and reliable diagnosis, tracking and study of modern isolates, vectors and interactions with the host organism. The potential of R. akari to be transmitted by other vectors underlines the need to identify outbreaks in unexplored regions and new environmental conditions. We describe the existing gaps in the modern understanding of the pathogenesis of smallpox rickettsiosis, its epidemiology and the genetic diversity of R. akari. We propose a list of research studies needed to improve the understanding of this neglected rickettsiosis and its etiological agent. akari transmitted by other vectors emphasizes the need to identify disease outbreaks in unexplored regions and in new environmental conditions. We describe the existing gaps in the modern understanding of the pathogenesis of smallpox rickettsiosis, its epidemiology and the genetic diversity of R. akari. We propose a list of research studies needed to improve the understanding of this neglected rickettsiosis and its etiological agent. akari transmitted by other vectors emphasizes the need to identify disease outbreaks in unexplored regions and in new environmental conditions. We describe the existing gaps in the modern understanding of the pathogenesis of smallpox rickettsiosis, its epidemiology and the genetic diversity of R. akari. We propose a list of research studies needed to improve the understanding of this neglected rickettsiosis and its etiological agent.