Taken together, we define the interplay between ZIKV and the type I interferon system and identify three points of interaction between the virus and cells: ZIKV infection generates stimuli for the pattern‐recognition receptors RIG‐I and MDA5, and the viral NS5 protein blocks the ensuing antiviral response by antagonizing RLR signaling and STAT transcription factors that are involved in IFNAR signaling. Here, IFIH1 is linked to Zika virus infectious disease.