Dengue fever/dengue hemorrhagic fever (DF/DHF) has emerged as the most important mosquito-borne viral diseases in tropical areas. The dengue virus (DV) has become endemic in most tropical urban centers throughout the world, and DHF has appeared concomitantly with this expansion. Given the fact that intensity of DV replication during the early times of infection could determine clinical outcomes, which ranges from febrile illness (DF) to life-threatening disease (DHF), it is important to understand the impact of DV infection on innate immunity. Interstitial dendritic cells (DCs) are believed to constitute the first line of the innate host defense against invading DV at the anatomical sites where it replicates after the initial bite by infected mosquito. Early activation of natural killer (NK) cells and type-I interferon-dependent immunity may be also important in limiting viral replication at the early times of dengue infection. The ability of infecting DV to counter the innate antiviral immunity might account for differences in virulence observed between viral strains.