The picornavirus family contains several human pathogens including human rhinovirus (HRV) and hepatitis A virus (HAV). In the case of HRVs, these small single-stranded positive-sense RNA viruses translate their genetic information into a polyprotein precursor which is further processed mainly by two viral proteases designated 2A and 3C. The 2A protease (2Apro) makes the first cleavage between the structural and non-structural proteins, while 3C protease (3Cpro) catalyzes most of the remaining internal cleavages. It has been shown that both 2Apro and 3Cpro are cysteine proteases but their overall protein folding is more like trypsin-type serine proteases. Due to their unique protein structure and essential roles in viral replication, 2Apro and 3Cpro have been viewed as excellent targets for antiviral intervention. In recent years, considerable efforts have been made in the development of antiviral compounds targeting these proteases. This article summarizes the recent approaches in the design of novel 2A and 3C protease inhibitors as potential antiviral agents for the treatment of picornaviral infections.