The known late Cretaceous-Present South American land mammals, more than any other land fossils, demonstrate that macroevolutionary processes can only be understood if we have a prior knowledge of the historic biogeographical events. On this basis, the main events marking the history of South American land mammals are analyzed in relation to the geodynamic events that produced the successive geographical and climate-environmental South American changes. It was found a close relationship between the abiotic and biotic phenomena succeeded during the late Cretaceous-Present span. The mammals up to date known representing the early and late Cretaceous time interval pertain only to non-tribosphenic and pre-tribosphenic groups. Further, they are markedly endemic (to the familial level, and even to higher levels, e. gr. Gondwanatheria), which are interpreted as related to the long isolation of the Gondwanan Continent. This is recognized as the Gondwanan Stage, which followed the still non-recorded Pangean Stage. It has been recognized that there exists a long unrecorded span, representing at least most of the Maastrichtian and Danian. The next record, estimated as spanning the time between ca. 63.2 – 61.8 Ma, indicated that there had occurred a marked turnover, characterized by the replacement of the pre- and non-tribosphenic native mammals by the immigrant tribosphenid marsupials and placentals. Furthermore, the Patagonian locality of this age records the last non-tribosphenic gondwanatherian (Sudamerica ameghinoi) together with the first non-Australian monotreme (Monotrematum sudamericanum). On the one hand, it is obvious that during the unrecorded Maastrichatian-Danian span there existed connections both with North America and Australia (via Antarctica). On the other hand, the so marked endemism of marsupials and placentals indicated that the isolation of the South American continent had been acting from some time ago. This Isolation Stage was broken up during the late Eocene, permitting the immigration of hystricognathan rodents and platyrrhini monkeys —apparently from Africa—, and during the late Oligocene-early Miocene, permitting that some megalonychoid edentates emigrated to the West Indies. The final connection with North America occurred by the late Pliocene and through the Panamanian Bridge. It led to the Great American Biotic Interchange. It was preceded by some premonitory interchange, as island-hoppers, having the procyonid carnivores and the tardigrade edentates as the main heralds, respectively from North America and South America. The Megafaunal Extinction, succeeded around 10000 years before Present, and the subsequent entrance of the Sciuridae, Heteromyidae, and Geomyidae rodents, the lagomorph Leporidae, and the Soricidae insectivores, built up the present scenario characterizing the Neotropical Region. We estimate that at least 50% of the present genera descended from North American immigrants. This paleobiogeographical history indicates that South America is the only continent that preserves, as fossil or living, land mammals originated in any of the major continental blocks that differentiated from the late Triassic on, when the oldest mammals was recorded. Surprisingly, none of its extant land mammals represent any order proved to be originated in the South American continent when differentiated as such.