Sumoylation is a post-translational modification that was originally thought to only target nuclear proteins. Evidence has emerged, however, that the role of sumoylation is much more diverse: three plasma membrane proteins belonging to different protein families (glucose transporters, K(+) channels and metabotropic glutamate receptors) have been shown to be sumoylated. In addition, sumoylation of transcription factors, such as myocyte enhancer factor 2 (MEF2), was found to regulate synapse formation. A major role of sumoylation in other systems is to modify protein-protein interactions, and because protein interactions are particularly elaborate in the nervous system and crucial for synapse formation and function, sumoylation could constitute a major regulatory mechanism in neurons. In this review, we evaluate the available data and discuss possible roles for sumoylation in the regulation of crucial neurobiological processes, such as neuronal development and synaptic transmission.