The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) appeared during the evolution of vertebrates as a new mechanism for regulation of cell interactions. This large and abundant glycoprotein can exert steric effects at the cell surface that lead to the attenuation of cell-cell bonds mediated not only by NCAM but also a variety of other adhesion receptors. PSA-NCAM expression changes both as a result of developmental programs and physiological inputs. This global modulation of cell-cell attachment has been shown to facilitate cell migration, axon pathfinding and targeting, and plastic changes in the embryonic and adult nervous system.