Much of South America consists of diverse arid and semiarid regions characterized by high mammal endemism as a result of a complex interplay between place and lineage histories. In this review we summarize and highlight several biogeographical and ecological features of the small mammals of South America drylands, with special focus on the Monte Desert biome. We provide information on population characteristics, community structure, food and habitat use, and responses to disturbances. Major findings at different scales include the distinctiveness and high species turnover across South American drylands and Monte Desert ecoregions; synchronous population fluctuations with high variability between years; herbivory and omnivory as dominant trophic strategies; community structure organized through habitat and food segregation; and the importance of a landscape mosaic of grazed and ungrazed areas for maintenance of small and medium-sized mammal diversity.