Human pathogens from the Caliciviridae and Hepeviridae families impose a significant health and economic burden on our global society. Despite the substantial toll caused by viruses such as human norovirus, human sapovirus and hepatitis E virus (HEV), we currently have no specific antivirals available to combat these pathogens. The current therapies prescribed for chronic HEV infection are poorly tolerated and can result in treatment failure. Similarly, despite a significant body of research into identifying antivirals and vaccines for controlling human norovirus infections, none have achieved clinical approval. Safe and effective antivirals would be beneficial for the treatment of chronic norovirus and HEV infections and for prophylactic applications during outbreak and epidemic situations. The viral RNA-dependent RNA polymerase (RdRp) is a highly-conserved enzyme that is essential for viral replication and represents a prime antiviral target. Using in vitro polymerase activity assays and viral and replicon cell culture systems, this study describes the identification of broad-spectrum antivirals for further development against calicivirus pathogens and HEV. This study includes the first report of a class of hepatitis C virus (HCV) non-nucleoside inhibitors (NNIs) with cross-family antiviral activity, that demonstrated broad-spectrum inhibition of several calicivirus RdRps. A highly-conserved NNI binding pocket common to RdRps across the Caliciviridae was also identified, which represents a prime target for de novo antiviral design. A novel chemical scaffold is described with low micromolar activity against the human norovirus RdRp, that also demonstrated broad-spectrum activity against RdRps from across three Caliciviridae genera. Finally, an examination of antivirals previously developed against other viruses revealed three compounds with potent antiviral activity against replication of the HEV genotype 1 replicon, demonstrating that repurposing antivirals could provide an accelerated platform for HEV antiviral discovery. In conclusion, this thesis identified several broad-spectrum antivirals for further development against human pathogens such as HEV and norovirus, and a highly-conserved binding pocket for targeted norovirus antiviral design.