Changes in the concentration of intracellular Ca²⁺ ([Ca²⁺]_i) in response to various stimuli play a role in regulating numerous cellular processes, including the activation of gene expression. In neurons, the extraordinary diversity of the response to Ca²⁺ signaling depends on the location, intensity, and duration of the Ca²⁺ transient. Interestingly, Ca²⁺-dependent gene transcription appears to be sensitive both to increases in nuclear Ca²⁺, which occur after relatively intense stimuli, and to highly localized increases in Ca²⁺ near the sites of Ca²⁺ influx. Activation of intracellular signaling pathways by specific types of Ca²⁺ channels depends on localization of specific Ca²⁺ receptors close to the channel mouth. The dual regulation of signaling pathways by Ca²⁺ near channels and in the nucleus may permit neurons to precisely tailor transcriptional activation to specific types of electrical or chemical stimuli and at the same time ensure that only robust stimuli that generate nuclear Ca²⁺ elevations are converted into long-term changes in gene expression.