Homoplasy among morphological characters has hindered inference of higher level rodent phylogeny for over 100 years. Initial molecular studies, based primarily on single genes, likewise produced little resolution of the deep relationships among rodent families. Two recent molecular studies (Huchon et al., 2002, Mol. Biol. Evol. 19:1053-1065; Adkins et al., 2003, Mol. Phylogenet. Evol. 26:409-420), using larger samples from the nuclear genome, have produced phylogenies that are generally concordant with each other, but many of the deep superfamilial nodes were still lacking substantial statistical support. Data are presented here for a total of approximately 3,600 base pairs from portions of three different nuclear protein-coding genes, CB1, IRBP, and RAG2, from 19 rodents and three outgroups. Separate analyses, with data partitioned according to both genes and codon position, produced conflicting results. Trees obtained from all partitions of CB1 and RAG2 and those obtained from the first- plus second-position sites of IRBP were generally concordant with each other and the trees from the two recent studies, whereas trees obtained from the third-position sites of IRBP were not. Although the IRBP third-position sites represent only 1/9 of the total data set, combined analyses using either parsimony or likelihood resulted in trees in agreement with the IRBP third-position sites and in disagreement with the remaining 8/9 of the sites from this data set and the two recent multigene studies. In contrast, maximum-likelihood analysis using a site-specific rates model did recover a tree that is highly congruent with the trees in the two recent studies. If the IRBP third-position sites are removed from the current data set, then combined likelihood analyses obtain a tree that is highly congruent with those of the two recent studies. This analysis also provides, for the first time in a study of rodent phylogeny, robust statistical support for every bipartition, with just one exception. This tree divides rodents into two major clades. The first contains Myodonta (Muroidea plus Dipodidae) and the only unresolved trichotomy, from which descend Geomyoidea, Pedetidae, and Castoridae. On the other side of the root is a clade containing Sciuroidea plus Gliridae, and Hystricognathi. Some uncertainty remains on the placement of the root. Trees on which the Hystricognathi are the basal sister group to Myodonta, Geomyoidea, Pedetidae, and Castoridae are also found within a Bayesian 95% credible set, as estimated by Metropolis-coupled Markov chain Monte Carlo sampling.