β‐N‐Acetylhexosaminidases (GH20) and β‐N‐acetylglucosaminidases (GH84) are two genetically and functionally unrelated classes of glycosidases sharing the substrate‐assisted catalytic mechanism and architecture of their active sites. In humans, the deficiency of these enzymes causes severe neurodegenerative disorders such as Tay‐Sachs and Sandhoff lysosomal storage disorders (GH20) and Alzheimer's disease (GH84). For the research of the physiological functions of these enzymes, inhibitors selective for just one of the enzyme families must be employed in order to avoid the generation of complex phenotypes. The search for highly potent and selective inhibitors is based on the known common and distinct features of these enzyme groups, profiting from the crystal structures of the enzyme‐inhibitor complexes. In this chapter, the most studied inhibitor scaffolds such as NAG‐thiazoline, PUGNAc and GlcNAcstatins and their rationally designed analogues are described and discussed, providing an actual survey of the most efficient and selective compounds suitable for specific application.