During neural development and regeneration, chondroitin sulfate – the glycosaminoglycan (GAG) component of chondroitin sulfate proteoglycans (CSPGs) – has been proposed to guide axonal growth by acting as a chemorepellent. Chondroitin can be sulfated at several sites on its carbohydrate backbone – but can the pattern of CSPG sulfation affect its axon-guiding activity? On page 3083, Herbert Geller and colleagues suggest that it can. The authors show that chondroitin-4-sulfate, but not chondroitin-6-sulfate, repels the growing axons of mouse cerebellar granule neurons; this effect is abolished when chondroitin-4-sulfate is treated with chondro-4-sulfatase. Moreover, reactive astrocytes (which inhibit axonal growth) upregulate CSPG expression and produce more 4-sulfated than 6-sulfated GAG chains. Knocking down endogenous chondroitin-4-O-sulfotransferase 1 (C4ST1) in these astrocytes depletes 4-sulfation and reduces the repellent activity of the conditioned medium; conversely, astrocytes in which C4ST1 is overexpressed have more 4-sulfated GAG chains and are much less permissive to neuronal growth. Importantly, the expression of 4-sulfated GAG chains by reactive astrocytes is acutely increased in a mouse model of spinal injury. Thus, the site of chondroitin sulfation affects its role in axon guidance.