Activation of the transcription factor CREB is thought to be important in the formation of long-term memory in several animal species^,,. The phosphorylation of a serine residue at position 133 of CREB is critical for activation of CREB. This phosphorylation is rapid when driven by brief synaptic activity in hippocampal neurons. It is initiated by a highly local, rise in calcium ion concentration near the cell membrane, but culminates in the activation of a specific calmodulin-dependent kinase known as CaMK IV , which is constitutively present in the neuronal nucleus,. It is unclear how the signal is conveyed from the synapse to the nucleus. We show here that brief bursts of activity cause a swift (∼1 min) translocation of calmodulin from the cytoplasm to the nucleus, and that this translocation is important for the rapid phosphorylation of CREB. Certain Ca²⁺ entry systems (L-type Ca²⁺ channels and NMDA receptors) are able to cause mobilization of calmodulin, whereas others (N- and P/Q-type Ca²⁺ channels) are not. This translocation of calmodulin provides a form of cellular communication that combines the specificity of local Ca²⁺ signalling with the ability to produce action at a distance.