Signaling from synapse to nucleus is vital for activity-dependent control of neuronal gene expression and represents a sophisticated form of neural computation. The nature of specific signal initiators, nuclear translocators and effectors has become increasingly clear, and supports the idea that the nucleus is able to make sense of a surprising amount of fast synaptic information through intricate biochemical mechanisms. Information transfer to the nucleus can be conveyed by physical translocation of messengers at various stages within the multiple signal transduction cascades that are set in motion by a Ca(2+) rise near the surface membrane. The key role of synapse-to-nucleus signaling in circadian rhythms, long-term memory, and neuronal survival sheds light on the logical underpinning of these signaling mechanisms.