Due to the ongoing Zika virus (ZIKV) epidemic and unexpected clinical outcomes including Guillain-Barré syndrome and birth defects, there is an urgent need for animal model development. We evaluated infection and pathogenesis with contemporary and historical ZIKV strains in immunocompetent mice and transgenic mice lacking components of the innate antiviral response. Whereas 4 to 6 week-old wild-type, Irf3 −/−, Irf5 −/−, and Mavs −/−, mice showed no overt clinical illness, Irf3 −/− Irf5 −/− Irf7 −/− TKO and Ifnar1 −/− mice developed neurological disease and succumbed to ZIKV infection. Ifnar1 −/− mice sustained high viral loads in the brain and spinal cord, consistent with evidence that ZIKV causes neurodevelopmental defects in human fetuses. The highest viral loads were detected in the testes of Ifnar1 −/− mice, which is relevant to sexual transmission of ZIKV. This model of ZIKV pathogenesis will be valuable for evaluating vaccines and therapeutics, as well as understanding basic mechanisms of disease pathogenesis and immune evasion.