Glycosaminoglycans (GAGs) are important components of the extracellular matrix. They are involved in the regulation of cell–cell and cell–matrix interactions, and can influence cellular signals through interaction with growth factors and cytokines. The GAGs chondroitin sulfate (CS) and dermatan sulfate (DS) are enriched in the neural stem cell (NSC) niche and have been shown to be involved in the regulation of NSC proliferation and differentiation. Melitta Schachner and colleagues (p. 4051) now unravel the specific functions of these two GAGs in NSC biology by using transgenic mice that are deficient in the sulfotransferase enzymes that synthesise CS or DS. Deficiency in dermatan 4-O-sulfotransferase-1 (Chst14), which is required for DS synthesis, results in impaired NSC proliferation and neurosphere formation, as well as reduced neurogenesis. By contrast, the ablation of chondroitin 4-O-sulfotransferase-1 (Chst11) does not have these effects. In addition, the expression of epidermal growth factor receptor and fibroblast growth factor receptor 1 is upregulated in Chst14−/−, but not Chst11−/−, neurospheres. Thus, CS and DS have specific roles in the regulation of NSC biology. The authors suggest that DS generated by Chst14, but not CS, affects proliferation and differentiation of NSCs by modifying cell–cell and cell–matrix contacts, as well as the interaction between growth factor receptors with their respective ligands.