Human rhinoviruses (HRVs) comprise over 100 different serotypes and are the predominant cause of the common cold. Although HRV infections are generally mild and self-limiting, they can also be associated with more serious illnesses, specifically, exacerbation of disease in individuals with underlying respiratory disorders. HRVs are a group of small single-stranded positive-sense RNA viruses that translate their genetic information into a polyprotein precursor that is mainly processed by a virally encoded 3C protease (3Cpro; EC 3.4.22.28) to generate functional viral proteins and enzymes. The enzymatic activity of HRV 3Cpro is essential to viral replication, and is distinguished from most other proteases by the fact that it has a cysteine nucleophile but with a chymotrypsin-like serine protease folding. This unique protein structure together with its essential role in viral replication made the 3Cpro an excellent target for antiviral intervention[1].