Yellow fever is an arthropod-borne disease with symptoms ranging from mild fever to acute hepatonephritis, hemorrhages and shock often fatal. The pathophysiology of severe yellow fever in humans and in monkeys susceptible to the virus is largely unknown. Yellow fever virus replicates in Küpffer cells and in hepatocytes in the liver. The degree of severity in yellow fever disease is linked to different factors related to virus virulence and to host susceptibility. A better knowledge of the complex interactions between the virus and the host is requested before initiating new actions in prophylaxy and therapy against yellow fever.