Although there have previously been hints that heparan sulphate proteoglycans (HSPGs) are important for axon guidance, as they are for many other biological processes, there has been little in vivo evidence for interaction with known axon-guidance pathways. Genetic analyses of fly, mouse, nematode and zebrafish mutants now confirm the role of HSPGs in axon guidance and are beginning to show that they might have a key role in modulating the action of axon-guidance ligands and receptors.