Proteolytic processing of the coronavirus replicase polyproteins is essential for ongoing viral ribonucleic acid (RNA) synthesis. Therefore, the severe acute respiratory syndrome (SARS)-coronaviruses (SARS-CoV) proteases are attractive targets for the development of antiviral drugs to reduce viral replication and pathogenicity. The structure and activity of the coronavirus 3C-like protease (3CLpro) has already been elucidated, and the design of inhibitors to 3CLpro as therapeutics has been proposed. The chapter discusses SARS-CoV 3CLpro inhibitors that include covalent inhibitors, noncovalent inhibitors, and inhibitors from screening. SARS-CoV papain-like protease (PLpro) is considered an equally viable target to 3CLpro for drug design because both are essential for viral replication. However, PLpro has likely not been pursued because of the paucity of structural information. Several compounds have been identified that have shown inhibitory activity against SARS-CoV. However, no information regarding their mechanism of action or the corresponding target is known. Glycyrrhizin showed inhibitory activity for SARS-CoV replication with EC50 = 300 mg/L after virus absorption in Vero cells. Some glycyrrhizin acid derivatives were found to inhibit SARS-CoV replication in vitro with EC50 values ranging from 5 to 50 μM. Unfortunately, these compounds show high cytotoxity.