AbstractIt is well known that viruses, as obligate intracellular parasites, must use their hosts' metabolic machinery in order to replicate their genomes and form infectious progeny virions. What is less well known are the details of how viruses make sure that once all the necessary proteins are made, that they assume the correct configuration at the proper time in order to catalyse the efficient assembly of infectious virions. One of the methods employed by viruses to regulate this process is the proteolytic cleavage of viral proteins. Over the past several decades, studies in numerous laboratories have demonstrated that morphogenic proteolysis plays a major and essential role during the assembly and maturation of infectious poxvirus virions. In this review we describe the history of vaccinia virus proteolysis as a prototypic viral system. Copyright © 2006 John Wiley & Sons, Ltd.