Arthropod-borne Flaviviruses, such as dengue virus (DENV), West Nile virus (WNV) and yellow fever virus (YFV), are a cause of major health and economic concerns, cumulatively infecting hundreds of millions of people worldwide. These viruses can cause a broad range of diseases in human, frequently leading to a lethal outcome. Although no vaccine or treatments currently exist to prevent or treat many Flavivirus infections, the YF 17D attenuated strain is the sole exception and is one of the most efficient vaccines ever developed. However, the molecular mechanisms responsible for its strong induction of immune responses are not known. Here, we propose to take advantage for the first time of a humanized immune system mice model that recapitulates the YF lethal course of infection observed in humans. Uncovering novel virus-host immune signatures that define YF pathogenesis in vivo can provide valuable information for the rational design of innovative vaccine strategies against some of the more challenging human pathogens.