Abstract: Infection by human rhinovirus (HRV) causes upper and lower respiratory tract disease with varying degrees of virulence. The molecular basis of diversity was examined by completing the genome sequences for all known serotypes (n=99) as well as novel field samples. Superimposition of capsid crystal structure and optimal-energy RNA configurations established the alignments. The phylogeny revealed conserved motifs, Glade-specific diversity including a potential new species (clade-D), pan-genome mutations in field isolates, and unexpected recombination that contributes to heterogeneity. A spacer tract near a 5?-UTR cloverleaf was hypervariable, and in analogy with poliovirus, may be associated with virulence. A previously unidentified configuration consistent with non-scanning internal ribosome entry may account for rapid protein translation.