The discovery of the intercellular messenger nitric oxide (NO) stimulated new concepts of how synaptic plasticity could be induced in the nervous system. While initial reports found evidence that NO is of importance for the formation of long-term potentiation of synaptic transmission (LTP) and spatial learning in rats, later reports failed to confirm these results. Novel approaches such as deletion of the gene that encodes NO synthase in mice showed that the neuronal and the endothelial isoforms are expressed in neurones. Deletion of both isoforms reduced the inducibility of LTP. Furthermore, novel selective inhibitors of NO synthase impaired spatial learning. These results support the hypothesis that NO plays an important role in synaptic transmission and explain some but not all previously contradictory results.