The recent unprecedented spread and severe pathogenic features of Zika virus (ZIKV) in the Americas have highlighted this emerging pathogen as a major threat to global public health. Substantial efforts have been devoted to examining novel aspects of ZIKV transmission and pathogenesis in the Americas. However, these studies are limited by the lack of ZIKV data from Africa, where the virus was discovered over 70 years ago and is believed to have been silently circulating for decades. The prevalence and importance of ZIKV infections and the properties of strains that circulate in East Africa, where the virus was first discovered, are unknown. In this thesis, we examined ZIKV circulation over two decades and its contribution to febrile illness in Kenya using two unique cohorts. Further, we interrogated the role of the innate antiviral type-I interferon (IFN-I) response in the restriction of ZIKV strains from Africa and the Americas, where there appears to be a difference in disease associated with ZIKV infections. First, we screened plasma collected 2-12 months after febrile and/or exanthematic illness in densely populated, urban regions of Western and coastal Kenya between 1993-2016 for binding and neutralizing antibodies to distinguish ZIKV and Dengue virus (DENV) responses, which we found were common in coastal Kenya. We identified two subjects with durable ZIKV-specific antibodies and two cases with evidence for both ZIKV and DENV infections. The cases span an ~20-year period (1994-2013), suggesting a very low, persistent burden of ZIKV in two major urban areas in East Africa, with no evidence for ZIKV outbreaks. Given that ZIKV is present at low levels in large population centers in Kenya, these findings highlight the need for continued arboviral surveillance and improved platforms for arboviral detection. Next, we designed a phage-display based serological screening tool (PhIP-Seq) to specifically identify cases of prior ZIKV exposure by detection of ZIKV-specific IgG antibodies. Using PhIP-Seq, we identified preliminary ZIKV-specific peptides that are characteristic of ZIKV infection in non-human primate sera. Future studies are needed to validate this approach with a larger panel of human sera using bioinformatics tools that account for the high-dimensional aspects of PhIP-Seq data. We demonstrated that PhIP-Seq can also be used to map the epitopes of monoclonal antibodies directed against pathogens in the phage library. We successfully mapped the epitopes of twenty-two HIV-specific monoclonal antibodies isolated from three HIV-infected Kenyan subjects. Finally, we compared the IFN-I-mediated restriction of ZIKV strains isolated in Africa and the Americas and examined the contribution of interferon-induced transmembrane protein-3 (IFITM3), the first interferon-stimulated gene (ISG) reported to inhibit ZIKV, to the overall IFN-I response against ZIKV. We identified a robust IFN-I-mediated antiviral effect on ZIKV infection in a commonly used cell line to study ZIKV replication, A549 cells. The effects of IFN-I on ZIKV replication varied by viral lineage in our panel of nine ZIKV strains. African-lineage strains, which have not been linked to pathogenesis, were less sensitive to IFNα (p=0.049) and IFNβ (p=0.09) than Asian-lineage strains, which have seeded the American pathogenic outbreak. We did not identify a role for IFITM3 in the IFN-I-mediated restriction of ZIKV, suggesting that other ISGs are important mediators of the IFN-I response against ZIKV in A549 cells. Given the potent antiviral effect of IFN-I on ZIKV in these cells, they present an opportunity for the discovery of novel antiviral ISGs against ZIKV. To this end, we used A549 cells to develop a CRISPR screen that may be used to identify ISGs that inhibit ZIKV. Preliminary findings from three screens highlight the promise of this approach for identifying ISGs that inhibit ZIKV. Future work may identify as-yet undiscovered ISGs that restrict ZIKVs as well as those that have activity against other related flaviviruses and cytopathic viruses.