Heparan sulfate (HS) regulates several extracellular signalling pathways during development, such as the FGF and Wnt pathways. The binding of HS to these ligands and their receptors is regulated by its precise 6-O-sulfated structure, but what controls this `HS code' and thus the signalling functions of HS? On p. 3327, Ai and colleagues provide the first evidence that the extracellular HS 6-O-endosulfatases SULF1 and SULF2 are essential in vivo regulators of HS-mediated developmental signalling. The researchers identify an oesophageal primary neuronal innervation defect in Sulf1-/-Sulf2-/- double-null mice and show that aberrant glial cell line-derived neurotrophic factor (GDNF) signalling causes this defect. Other experiments indicate that SULF1 and SULF2 are expressed in the developing oesophagus, that they function redundantly as the major regulators of HS 6-O-desulfation, and that Sulf activity decreases GDNF binding to HS (GDNF binds to HS through its 6-O-sulfate groups). The researchers conclude,therefore, that Sulf activity enhances GDNF signalling in normal mice,consequently promoting neurite sprouting in the embryonic oesophagus.