Background Currently, Caliciviridae include one genus Calicivirus containing strains with distinct structural and genomic features. Our recent phylogenetic analyses of caliciviruses (CVs) revealed five distinct genetic clusters (genogroups) within Caliciviridae corresponding to differences in genome organization. Aim To determine whether these genetic clusters correspond to differences at the genus, family, or other taxonomic level. Methods Caliciviridae and Picornaviridae are members of the same virus superfamily and genera within Picornaviridae are well characterized. Available genomic sequences of CVs and of prototypes representing different picornavirus genera were collected. Corresponding regions of the genomes were submitted to sequence analyses. Nucleotide and predicted amino acid sequences were aligned using CLUSTAL V. After alignments were optimized, they were bootstrapped for phylogenetic analyses (N=1,000). The phylogenetic package PHYLIP v3.5 utilizing parsimony, distance and maximum likelihood methods was used to estimate the phylogenetic relationships among strains. Results Utilizing conserved genomic sequences for the analyses, only major groups of CVs were separated with confidence (≥0.95 probability), including human small round-structured viruses (SRSVs), hepatitis E virus (HEV), animal CVs (AnCVs) and Sapporo-like human CVs. Among Picornaviridae, genera were separated. Analysis of the most variable genomic region revealed greater details of relationships among CVs. The five main genetic clusters (SRSVs, Sapporo-like HuCVs, HEV, vesicular exanthem of swine virus-, and rabbit-like AnCVs) showed distances corresponding to those observed among picornavirus genera. Conclusion Our findings support a reclassification of the genus Calicivirus in the Caliciviridae into five distinct genera. This conclusion is supported by observed differences in virion morphology, genome organization, and amino acid motifs at the sequence level. These results have implications for host and other ecologic relationships isolating the genera.