South America is a high biodiversity continent with five out of 13 countries considered megadiverse. Many major groups within this fauna exhibit high diversity, including non-marine molluscs. With at least 1401 known species, South American molluscs are seriously understudied. The aim of this paper is to review the conservation status of non-marine molluscs in South America, pointing out significant gaps in knowledge and suggesting possible future directions. According to the most recent IUCN Red List only 231 South American non-marine molluscs have been evaluated, with 84 (36%) categorized as Data Deficient. The main knowledge gaps are in taxonomic inventory, especially in unexplored areas, information about current and historic distributions and population sizes, and basic ecological information. Implementation of integrative taxonomy, ecological and distributional studies, exploration of areas and groups as yet largely ignored, development of researcher networks and improvement of public and political awareness and concern about these important and diverse animals are necessary actions for conservation of non-marine molluscs in South America to have any chance of success.