Viruses are some of the smallest biological entities on earth. They are also extremely pathogenic and can infect organisms from all three domains of life. The virus itself is a small 50 nm lipid-enveloped particle that contains a single-stranded positive-sense RNA genome that encodes for ten viral proteins, all of which are essential for viral infection, replication, and propagation. The HCV core protein is the least variable of all ten HCV proteins and highly conserved among the six major viral genotypes, making it an attractive target for novel therapeutics. Nucleic acid-based drugs offer numerous opportunities for both academic and industrial endeavors. Classical structural approaches such as X-ray crystallography probe large molecular ensembles.