C-Cluster enteroviruses (C-CEVs), consisting of Coxsackie A viruses (C-CAV1, 11, 13, 15, 17, 18, 19, 20, 21, 22, 24, 24v) and polioviruses (PV1, 2, 3), have been grouped together in relation to their genomic sequences. On the basis of disease syndromes caused in humans, however, C-CAVs and PVs are vastly different: the former cause respiratory disease, just like the major receptor group rhinoviruses (magHRV), whereas PVs, on invasion of the CNS, can cause poliomyelitis. It is assumed that the difference in pathogenesis of C-CEVs is governed predominantly by cellular receptor specificity. C-CAVs use ICAM-1, just like magHRV, whereas PVs uniquely use CD155. Both ICAM-1 and CD155 are Ig-like molecules. Remarkably, based on a phylogenetic analysis of non-structural proteins, CAV 11, 13, 17 and 18 are interleaved with, rather than separated from, the three PV serotypes, e.g. PV1 is more closely related to CAV18 that to PV2. This observation suggests that PVs may have emerged from a pool of C-CAVs by evolving a unique receptor specificity. We have been studying virion structure, virion/receptor interactions, genetics, and the molecular biology of C-CEVs with the objective of identifying the molecular basis of phenotypic diversity of these viruses. Of particular interest is the prospect that C-CEVs can be genetically manipulated to switch their receptor affinity: from CD155 to ICAM-1 for PVs, or from ICAM-1 to CD155 for C-CAVs. We propose a hypothesis that in a world free of poliovirus and anti-poliovirus neutralizing antibodies C-CAVs would be given a greater chance to switch receptor specificity from ICAM-1 to CD155 and thus, to evolve gradually into a new polio-like virus.