Dengue virus is sensed in mammalian cells by Toll-like receptors and DExD/H box RNA helicases, triggering a Type 1 interferon response. Interferon acts upon infected and noninfected cells by stimulating the JAK/STAT signaling pathway resulting in the activation of interferon stimulated genes that lead cells toward the establishment of an antiviral response. The recognition of the importance of this rapid protective response should come with the realization that dengue virus would circumvent the interferon response to propagate in the host. There is recent, mounting evidence for mechanisms encoded by the dengue virus that weaken interferon signaling. Nonstructural proteins expressed separately or in replicon vectors block phosphorylation and down-regulate expression of major components of the JAK/STAT pathway, causing reduced activation of gene expression in response to IFNalpha/beta interferon. As our understanding of viral-host interaction increases, opportunities for improved biological models and therapeutics discovery arise.