The plasma membrane of eukaryotic cells is coated with carbohydrates. By virtue of their extracellular position and recognizable chemical features, cell surface glycans mediate many receptor-ligand interactions. Recently, mammalian extracellular hydrolytic enzymes have been shown to modify the structure of cell surface glycans and consequently alter their binding properties. These cell surface glycan remodeling events can cause rapid changes in critical signal transduction phenomena. This Review highlights recent studies on the roles of eukaryotic extracellular sialidases, sulfatases, and a deacetylase in regulation of intracellular signaling. We also describe possible therapies that target extracellular glycan remodeling processes and discuss the potential for new discoveries in this area.