SARS-CoV (severe acute respiratory syndrome-associated coronavirus) caused infection of ~8000 people and death of ~800 patients around the world during the 2003 outbreak. In addition, picornaviruses such as enterovirus, coxsackievirus and rhinovirus also can cause life-threatening diseases. Replication of picornaviruses and coronaviruses requires 3Cpro (3C protease) and 3CLpro (3C-like protease) respectively, which are structurally analogous with chymotrypsin-fold, but the former is a monomer and the latter is dimeric due to an extra third domain for dimerization. Subtle structural differences in the S2 and S3 pockets of these proteases make inhibitors selective, but some dual inhibitors have been discovered. Our findings as summarized in the present review provide new potential anti-coronavirus and anti-picornavirus therapeutic agents and a clue to convert 3CLpro inhibitors into 3Cpro inhibitors and vice versa.