Polysialic acid (polySia) is an atypical posttranslational modification that is primarily found on the neural cell adhesion molecule (NCAM) and acts as a key regulator of cell–cell interactions and cell migration. Increased levels of the polymeric carbohydrate have previously been associated with several types of tumour. But how does polySia affect cell motility and what is its role in tumour progression? On page 3279, Herbert Hildebrandt and co-workers now present answers to these questions. Using a 2D scratch assay, they show that the presence of polySia enhances the migration of neuroblastoma cells. By contrast, the loss of polySia reduces tumour cell motility. Interestingly, only those cells that are in contact with others – but not single cells – show this effect. In addition, the removal of polySia promotes the formation of new focal adhesions in an NCAM-dependent manner. As NCAM primarily localises to areas of cell–cell contact and is not found in focal adhesions, it must mediate this effect indirectly through the activation of signalling pathways, the authors suggest. Together, these data support a role for polySia as a negative regulator of NCAM-induced signalling from cell–cell contacts to focal adhesions. This crosstalk between cell–cell and cell–matrix interactions is important for the regulation of cell migration and adhesion and, subsequently, is involved in promoting the motility of tumour cells.