The flavivirus non-structural protein, NS1, is an unusual viral gene product. Despite the recent unveiling of its atomic structure (Akey et al., 2014), and a growing list of host molecules with which it has been found associated, the primary function of NS1 remains elusive. It assumes many diverse roles including direct participation in the flaviviral replication complex and virion maturation. In its secreted form it is a hexameric lipoparticle that is involved in systemic immune and endothelial cell modulation. In this review we highlight recent advances in elucidating the molecular mechanisms underpinning NS1 function and present the current state of play and some future prospects for NS1 targeted antiviral strategies. This article forms part of a symposium on flavivirus drug discovery in Antiviral Research. •NS1 is a multi-functional protein with distinct structural forms offering a range of targets for inhibitor development.•Identification of NS1 as a TLR4 agonist suggests the possibility of repurposing sepsis drugs for the treatment of severe dengue.•As an integral feature of NS1 maturation and trafficking, glycosylation is a validated NS1-directed antiviral target.•Secreted NS1 is a soluble lipoparticle – perturbation of lipid metabolism has been a focus of ongoing flavivirus research.•NS1 structural homology with the complement control protein (CCP) offers opportunities for antiviral development.