Human norovirus is a leading cause of acute gastroenteritis (AGE) worldwide and is estimated to be responsible for over 200,000 deaths each year. Norovirus infections are estimated to cost $60 billion in societal costs globally each year. Yet despite the substantial health and economic burden of norovirus, there is no vaccine or norovirus-specific antiviral approved for clinical use. Effective norovirus therapies are highly desired, particularly for the treatment of chronic norovirus infections, or for prophylaxis to limit outbreaks and protect high-risk groups, including the immunocompromised. Several direct-acting antivirals (DAAs) and host-targeted therapies have demonstrated inhibitory activity against noroviruses in vitro and in vivo, however none of these compounds have progressed through clinical trials. Therefore, this thesis aimed to discover new antivirals and expand the repertoire of compounds with the potential to be further developed for the treatment of norovirus infections. In the first study, RNA-sequencing was performed to provide insights into norovirus pathogenesis and to help identify new host targets that could be explored antiviral development. We found that norovirus infection dampens the transcriptional profile of several genes involved in MHC class I antigen presentation, likely for immune evasion. We also observed a significant reduction in TLR7 expression which could represent a mechanism to avoid recognition by the host. To explore this further, we screened several Toll-like receptor (TLR) agonists, currently in clinical trials for antiviral therapy, against norovirus and found that these compounds potently inhibit infection in vitro. Here we discovered a new target for norovirus antivirals. Lastly using in vitro antiviral assays against several caliciviruses, we discovered a new nucleoside analogue (NA), called NITD008, which represents the most potent NA described in the literature to date and a strong candidate for continued development. The new anti- norovirus compounds described in this thesis could be used as scaffolds for the generation of derivatives with improved drug properties or be used in combination with other compounds for improved efficacy. Overall, this thesis involved a multi-faceted approach to antiviral discovery which has increased the available compounds in the pre-clinical pipeline for norovirus therapy.