Dengue virus (DENV) causes 100 million symptomatic cases annually and represents a growing public health threat as the geographic range of its vector mosquitoes expands. However, there are no treatments for dengue disease and limited vaccine options. The antibody response to DENV represents a major barrier in developing safe and effective clinical interventions; intermediate IgG antibody titers are correlated with more severe dengue disease. The prevailing theory behind this observation is a phenomenon known as antibody-dependent enhancement (ADE) of DENV, where DENV uses non-neutralizing IgG antibodies to enter target cells expressing Fc gamma receptors (FcgR). Beyond the requirement of Fc-FcgR interactions, functional requirements of ADE of DENV infection are unknown because existing studies are unable to establish cause and effect. However, functional requirements of DENV in the absence of antibodies infection have been robustly identified via genome-wide CRISPRknockout screens. Therefore, I used genome-wide CRISPR knockout screening in a model amenable to efficient infection only via ADE to investigate the functional requirements of ADE. By performing genome-wide and follow-up targeted CRISPR screens, I identified and validated novel candidate host factors specifically required for ADE. Specifically, I found that knockout of SV2B or TBC1D24, genes typically involved in vesicle trafficking and regulated secretion in the nervous system, reduced the level of infection via ADE, but not direct infection, and trans-complementation of these genes restored ADE efficiency to wild-type levels. Knockout of these genes reduced ADE efficiency in various contexts, including in assays using sera from DENV-experienced donors, fully infectious virus of each serotype, and multiple cell lines. Finally, knockout of these genes reduced binding of antibody-virion complexes to cells without affecting FcgR expression levels. Overall, these studies show SV2B and TBC1D24 are required for ADE of DENV infection and suggest a role for endocytic pathways typically involved in synaptic vesicle trafficking in this non-canonical viral uptake pathway. The findings described in this thesis are a first step toward increasing fundamental knowledge of the biology of this alternative infection route implicated in disease, which eventually could be exploited to inform therapeutic approaches.