Nanotoxicology is a new and emerging field of research that has received considerable attention over the past few years. To date, most nanotoxicological studies remain poorly and unevenly distributed with most research restricted to a narrow range of test species such as daphnids. Freshwater crabs (Potamonautidae) have been a prominent model invertebrate in a variety of biological disciplines. Potamonautes spp. are prevalent in rivers of the south-western region of the Western Cape of South Africa. They occupy a prominent position in aquatic ecosystems where they play an important role in the processing of organic material. Promising results have been obtained when Potamonautes spp. were used for nanotoxicity assessment following exposures to silver nanoparticles (AgNPs) and climatic stressors. Although still in its infancy, there is a strong potential for Potamonautes spp. to provide a valuable contribution to nanotoxicity. The purpose of this chapter is to illustrate the potential of using Potamonautes spp. as important freshwater model organisms for nanotoxicology studies. The advantages of Potamonautes spp. in identifying endpoints of toxicity and in elucidating mechanisms of toxicity are presented. Additionally, the gaps in nano-toxicological research and recommendations for future research initiatives are addressed.