Noroviruses are single-stranded RNA viruses. They encode a protease that cleaves a viral polyprotein at specific sites to produce mature viral proteins. In addition, the protease also binds to viral RNA, and thus is thought to regulate viral replication. However, to date no structural information is available for protease-substrate complexes that might explain the interactions made by peptide residues P’-side of cleavage junctions or RNA. Here I report the work carried out to characterize these interactions in human norovirus protease using X-ray crystallography. The protease was successfully expressed, purified and the crystallization conditions were optimized to grow crystals for structure determination. Unfortunately, RNA and peptide electron density were not observed in co-crystal structures. The packing of protease molecules in one of the crystal forms shows the interaction of protease C-terminal residues with the peptide-binding groove of a neighboring molecule in the crystal, thereby providing the view of a protease-product complex.