The temperate zone of the southwestern Atlantic Ocean (23–42°S), which includes the Patagonian Shelf Large Marine Ecosystem and the Subtropical Convergence Zone, is one of the most productive areas of the Southern Hemisphere. Key features of this region are a wide continental shelf, the convergence of cold and warm currents, and continental freshwater input of the La Plata River. The Uruguayan marine and estuarine waters are at the core of this zone. The marine and estuarine bivalve fauna of Uruguay has received good attention since the publication of the Voyage of Alcide d'Orbigny (1834–1846). Here we provide an overview of taxonomic, faunistic and biogeographic issues, identifying knowledge gaps and highlighting priorities for future research. The main threats for that fauna are discussed, with emphasis on species of current or potential socioeconomic interest. Of the 231 species reported from the area, only four species are strictly estuarine: Erodona mactroides Bosc, 1801, Tagelus plebeius (Lightfoot, 1786), Brachidontes darwinianus (d'Orbigny, 1842) and Mytella charruana (d'Orbigny, 1842). All of these have large biomasses, as is also the case for the marine eurihaline Mactra isabelleana d'Orbigny, 1846. A total of 112 deep-sea species (i.e., living deeper than 200 m) are recorded for the region, including almost every known group occurring elsewhere in deep-sea basins, with the exception of sunken wood associated species. Of these, 38 have been recorded only from the Argentine Basin. Some new records are preliminarily reported and discussed, including Acharax Dall, 1908 (Solemyidae), Lucinoma Dall, 1901, Graecina Cosel, 2006 (Lucinidae), and Callogonia Dall, 1889 (Vesicomyidae), all from the continental slope. A total of 19 warm and warm/temperate bivalve species have their southern distribution boundary in Uruguayan waters associated to warm waters of/or derived from the Brazil Current, including species distributed from the U.S.A. to Uruguay or from southeast Brazil to Uruguay. On the other hand, at least eight exclusively cold-water bivalves exhibit their northernmost distribution boundary off La Plata River; their occurrence there is associated with offshore sub-Antarctic waters. Uruguayan waters represent a critical biogeographical and ecological crossroads because of the complex interaction of currents and water masses. This region is thus particularly well suited as a system for the study of processes underlying biodiversity patterns. Pending challenges in taxonomic and biogeographic research will be successfully addressed only if multinational collaborative initiatives are undertaken in a framework of integrative taxonomy.