Until recently, the family Picornaviridae consisted of five established genera (36). Enteroviruses, rhinoviruses, and hepatoviruses include human pathogens; foot-and-mouth disease viruses of ungulates are the most important aphthoviruses; and cardioviruses are found mainly in rodents (48). Following the early studies of Loeffler and Frosch on foot-and-mouth disease viruses (32), work on enteroviruses started in the early years of this century, when Landsteiner and Popper demonstrated, by injection of a filtrate into monkeys, that poliomyelitis is caused by viruses (31). However, it was 40 years before a new, related virus group was discovered (11). These were the coxsackieviruses, which characteristically could induce disease in newborn mice. Following the introduction of tissue culture systems (14) for virus propagation, several viruses which shared physicochemical properties (solvent-resistant, acid-stable particles) with polio-and coxsackieviruses, but grew exclusively in cell culture, were isolated. These were called ECHO (enteric, cytopathogenic, human, orphan) viruses (9). The three subgroups, plus the new enterovirus types 68 to 71, include more than 60 serotypes and, together with several simian, bovine, and porcine strains, comprise the Enterovirus genus (25). However, a wide range of evidence, detailed below, shows that two echoviruses have distinct biological and molecular properties. These, echoviruses 22 and 23, have recently been assigned to a sixth picornavirus genus, Parechovirus, and have been renamed human parechovirus 1 and 2 (HPEV1 and HPEV2), respectively (29). Here we review how parechoviruses relate to other members of the Picornaviridae family. Previously studied picornaviruses have a single-stranded RNA genome of positive polarity, 7,100 to 8,500 nucleotides long, which is packaged into an icosahedral capsid made up of 60 copies of each of the capsid proteins VP1 through VP4 (48, 57). Genomic RNA is modified by the covalent attachment of a small protein (VPg; 20 to 25 amino acids) to the 5Ј terminus. The genome can be considered to have four distinct domains. A 5Ј untranslated region (5ЈUTR) precedes a single open reading frame, downstream of which there is a 3ЈUTR and a poly(A) tract. Ten, 11, or 12 proteins are encoded by different picornaviruses as shown in Fig. 1. The single polyprotein encoded by the genome is processed by a cascade of proteolytic events, instigated by virus-encoded enzymes, to give precursor molecules and then the final discrete proteins (40, 50). In several cases, the precursors themselves have important functional roles in virus replication. For instance, while the majority of processing events are brought about by 3C pro , cleavages in the capsid region appear to require 3CD pro , the precursor of