Phylogenetic relationships based on 801 base pairs (bp) of the mitochondrial cytochrome b gene are examined for eight genera and 28 species of the akodontine tribe of South American murid rodents. The akodontine tribe comprises some 35% of the total diversity of the subfamily Sigmodontinae, but the current taxonomy at virtually all levels is uncertain because of inadequate generic diagnoses and assessments of variation and trends in traditional morphological characters. Monophyly of the tribe cannot be resolved by the sequence data, based on comparisons to outgroup taxa in three other tribes (Oryzomyini, Phyllotini, and Thomasomyini). However, highly corroborated monophyletic units within the group are obtained in a variety of both parsimony and distance analyses. These include a redefined and numerically dominant genus Akodon (with Microxus and Hypsimys as synonyms), Bolomys, Lenoxus, Oxymycterus, and a strongly supported assemblage that includes the central Andean Chroeomys and ‘Akodon’ andinus and the southern Abrothrix, ‘Akodon’ olivaceus, and the long-clawed mice of the genera Notiomys, Geoxus, and Chelemys. Sequence divergence within species is typically less than 5%, although levels can reach 10% for some highly polytypic forms. Divergence among genera within the tribe reaches 35% in corrected estimates, a level that is as great as that among representatives of different tribes. Changes in the current classification of akodontines are suggested based on these data, and the timing and place of origin of the tribe and its radiation is discussed.