A novel coronavirus has been identified as the causative agent of severe acute respiratory syndrome (SARS). The viral main proteinase (M~(pro), also called 3CL~(pro)), controlling the activities of the coronavirus replication complex, represents an attractive target for therapy. A homology model for SARS coronavirus (SARS-CoV) M~(pro), which is based on crystal structures for human coronavirus (strain 229E) M~(pro) and for an inhibitor complex of porcine coronavirus (transmissible gastroenteritis virus, TGEV) M~(pro) are reviewed. The structures reveal a remarkable degree of conservation of the substrate-binding sites, which is further supported by recombinant SARS-CoV M~(pro)-mediated cleavage of a TGEV M~(pro) substrate. Molecular modeling suggests that available rhinovirus 3C~(pro) inhibitors may be modified to make them useful for SARS therapy.