: Smallpox is an infectious disease unique to humans, caused by a poxvirus. It is one of the most lethal of diseases; the virus variant Variola major has a mortality rate of 30%. People surviving this disease have lifelong consequences, but also assured immunity. Historically, smallpox was recognised early in human populations. This led to prevention attempts: variolation, quarantine and the isolation of infected subjects, until Jenner's discovery of the first steps of vaccination in the 18(th) century. After vaccination campaigns throughout the 19(th) and 20(th) centuries, the World Health Organization declared the eradication of smallpox in 1980. With the development of microscopy techniques, the structural characterisation of the virus began in the early 20(th) century. In 1990 the genomes of different smallpox viruses were determined; viruses could be classified in order to investigate their origin, diffusion and evolution. To study the evolution and possible re-emergence of this viral pathogen, however, researchers can only use viral genomes collected during the 20(th) century. Cases of smallpox in ancient periods are sometimes well-documented, so paleomicrobiology and more precisely, the study of ancient smallpox viral strains could be an exceptional opportunity. The analysis of poxvirus fragmented genomes could give new insights on the genetic evolution of the poxvirus. Recently, small fragments of the poxvirus genome were detected. With the genetic information obtained, a new phylogeny of smallpox virus was described. The interest of conducting studies on ancient strains is discussed, in order to explore the natural history of this disease. This article is protected by copyright. All rights reserved.