Calcium ions are ubiquitous second messengers that control diverse cellular functions. The versatility of Ca(2+) arises both from the ability of cells to employ a range of mechanisms to generate stimulus-induced Ca(2+) signals with defined characteristics and the existence of a large repertoire of Ca(2+) receptive proteins that mediate the effects of Ca(2+). In neurons, the regulation of gene expression by electrical activity-induced increases in Ca(2+) is critical for the long-term maintenance of neuronal adaptive responses. Different patterns of synaptic activity are able to generate Ca(2+) signals varying in their amplitude, temporal profile, spatial properties and source or site of entry. The information embedded in Ca(2+) signals is decoded by Ca(2+)-responsive transcriptional regulators, including protein kinases, phosphatases and transcription factors, with differing Ca(2+) sensitivities, kinetics of activation and deactivation, and subcellular localisation. The coordinated control of many transcriptional regulators by Ca(2+) signals determines the qualitative and quantitative nature of the genomic response.