Dengue virus (DENV) is a rapidly-spreading mosquito-borne (+)RNA virus that is currently endemic in over 100 countries and is responsible for a major public health burden. Despite this, there are no approved antiviral therapeutics available. The DENV non-structural protein 1 (NS1) plays critical roles in viral RNA replication, infectious virus particle production and viral pathogenesis and has emerged as a major target in the development of vaccines and antivirals. Towards the identification of DENV non-structural protein 1 (NS1)-host factor interactions that can serve as antiviral drug targets, we have mapped the proteomic composition the NS1 microenvironment in live infected cells using an APEX2 proximity labelling-coupled quantitative proteomics approach in conjunction with an APEX2-tagged reporter virus (DENV2-NS1-APEX2). An siRNA screen targeting the top 50 identified NS1-proximal host factors was performed to identify a panel of host factors that are required for DENV infection. It is hoped that the ongoing characterisation of a selection these validated hits using CRISPR/Cas9-mediated host gene knockout, protein-protein interaction assays and high-resolution confocal imaging analysis will reveal novel DENV NS1-host protein interactions that are essential to the viral replication cycle.