Mosquito-borne flaviviruses cause annual epidemics of encephalitis and viscerotropic disease worldwide. West Nile virus (WNV), a member of the Japanese Encephalitis virus (JEV) antigenic complex, is a major cause of viral encephalitis throughout the world [1]. In the United States, WNV has been estimated to cause more than 3 million infections, resulting in over 780,000 illnesses, 30,000 confirmed cases, and 1,100 deaths between 1999–2013 [2]. In contrast, dengue virus (DENV) is a major cause of virusinduced viscerotropic disease, with an estimated 50 to 100 million people infected each year and a total of 2.5 billion people worldwide are at risk of infection. There are currently no approved antiviral therapies or vaccines to combat or prevent WNV or DENV infection. WNV and DENV are closely related flaviviruses that are enveloped and possess a single strand positive-sense RNA genome of approximately 11kb in length. The genome is comprised of three structural proteins (C, prM/M, and E), which mediate virus attachment, entry, and encapsidation and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5), which form the replication complex to synthesize viral RNA (as reviewed in [3]). The NS proteins, including the viral RNA-dependent RNA polymerase NS5, form a replication complex that synthesizes negative-sense RNA intermediates, which subsequently serve as the template for synthesis of positive-sense RNA. The newly synthesized viral RNA is encapsidated, transported through the host secretory pathway, and released from the infected cell by exocytosis. The entire viral life cycle takes place within the cytoplasm. To combat infection, the host encodes pattern recognition receptors (PRR), residing within the cytoplasm and endosomal vesicles, which recognize pathogen-associated molecular patterns (PAMPs) and trigger inflammation and antiviral immune responses (Figure 1). Defining how viruses are sensed and the antiviral programs that are initiated to restrict virus replication have been areas of intense investigation over the past several years. In this article, we discuss contemporary research findings on how flaviviruses are ‘‘sensed’’by the host pattern recognition receptors and highlight a few outstanding questions on the mechanisms underlying host immune sensing and viral countermeasures.