Abstract This is the first cladistic analysis of sigmodontine rodents (Cricetidae, Sigmodontinae) based on nuclear and mitochondrial DNA sequences. Two most parsimonious cladograms (7410 steps in length; CI=0.199; RI=0.523) were discovered. Sigmodontinae appears well supported. Sigmodon is sister to the remaining living sigmodontines. It is shown that Euneomys is not a phyllotine and that the Reithrodon group is not monophyletic. Results corroborate that the abrothricines form a natural group that is not part of the akodont radiation. The akodontine tribe is well supported, and is composed of five main clades, whose limits and relationships are thoroughly discussed. For instance, the scapteromyines do not form a natural group and they fall within the akodontine clade. Additionally, I present some taxonomic judgments and comments on the historical biogeography of sigmodontines in the light of the newly discovered relationships. For example, five akodontine divisions are suggested: the Akodon, the Bibimys, the Blarinomys, the Oxymycterus, and the Scapteromys Divisions. It is shown that traditional hypotheses of sigmodontine historical biogeography are falsified by the recovered topology.