The family Palaeothentidae contains some of the dentally more specialized of the small-bodied marsupials of South America and was a clade almost equivalent with the Abderitidae in having been the most abundant caenolestoids. They were unquestionably the most diverse, containing two subfamilies, nine genera, and 19 species, with a distribution ranging from Colombia to Tierra del Fuego. The best and most continuous record of the Palaeothentidae is from Patagonian Argentina where eight genera and 17 species are recognized. There, the Palaeothentidae ranged in age from the Deseadan (later Oligocene) through the late Santacrucian (middle Miocene—the Santacrucian record lasting from about 19.4 m.y. to considerably less than 16.05 m.y. before the present). The family appears to have survived longer in Colombia. The palaeothentinePalaeothentes boliviensis(Bolivia) and the incertae sedis genus and speciesHondathentes cazador(Colombia) are the only taxa restricted to an extra-Argentine distribution.Two palaeothentid subfamilies are recognized. The subfamily Acdestinae is new and is erected to accommodate four genera and five species of herbivorous to frugivorous palaeothentids known from the Deseadan through the middle–late Santacrucian. Three of those genera are new (Acdestoides, Acdestodon, andTrelewthentes), as are three acdestine species placed in the generaAcdestodon, Trelewthentes, andAcdestis.The largely faunivorous Palaeothentinae includes four genera and 13 species; the generaPropalaeothentesandCarlothentesare new and new species are described for the generaPropalaeothentes(2) andPalaeothentes(3).Carlothentesis named for Ameghino's Deseadan speciesEpanorthus chubutensis, and Ameghino's genusPilcheniais resurrected to accommodate DeseadanP. lucina.New species include:Acdestodon bonapartei, Trelewthentes rothi, Acdestis lemairei, Palaeothentes marshalli, P. migueli, P. pascuali, andPropalaeothentes hatcheri.The Palaeothentinae contains more generalized palaeothentid species than does the Acdestinae, but also includes some very specialized forms. The most generalized known palaeothentid is the ColombianHondathentes cazador.Both the Acdestinae and Palaeothentinae have large- and small-bodied species;Palaeothentes arataewas the largest palaeothentid (about 550 g), andP. pascualin. sp. the smallest (about 50 g). The oldest known members of both subfamilies consist of five of the six largest palaeothentids.The evolutionary history of the Palaeothentidae is complicated by thick sequences containing no fossils, several lacunae in sequences that yield fossils, and a continent-wide distribution of localities. By far the densest and most continuous record of the family exists in the coastal Santa Cruz Formation of Patagonian Argentina. Three major clades exist within the Palaeothentidae: 1) the incertae sedis speciesHondathentes cazador; 2) the Acdestinae; and 3) the Palaeothentinae (including the new genusPropalaeothentes). The evolution of dental characters in these clades is documented with the aid of 719 new specimens (about 80% of the hypodigm of the family), most of which (about 90% of the new specimens) have precise stratigraphic data.Biostratigraphic study of the new samples was assisted by a new technique of temporal analysis of paleosols and by radiometric age determinations, the latter indicating that the upper part of the Pinturas Formation (16.6 Ma) is older than the lower part of the Santa Cruz Formation (16.4 Ma) and that the top of the marine Monte León Formation (Grupo Patagonica) is older than either (19.4 Ma).Fifty-two gnathic and dental characters were used to identify the taxonomy and to reconstruct the phylogeny of the Palaeothentidae. Analysis of sequencing of appearances of derived characters documents rampant convergences at all taxonomic levels and considerable phenotypic plasticity (variable percent representation of different mutable character morphs) in the organization of the palaeothentid dentition. Certain highly generalized character states survive for the duration of the family in some lineages, whereas others are phenotypically lost for a time and then reappear as a minor percentage of character variability. In general, replacement faunas of palaeothentids were morphologically more generalized than their antecedent forms. The high rate of character mutability and the survival and reappearance of generalized dental characters in the Palaeothentidae were probably related to massive events of pyroclastic deposition that periodically caused at least local extinctions of small mammal populations throughout the duration of the Patagonian middle Tertiary. Dental character regression indicates that palaeothentids arose prior to the Deseadan from a relatively large-bodied marsupial having generalized tribosphenic molars with more or less bunodont cusps; probably an unknown member of the Didelphidae.