Regucalcin (RGN/SMP30) was discovered in 1978 as a calcium (Ca(2+))-binding protein that contains no EF-hand motif of the Ca(2+)-binding domain. The name of regucalcin was proposed for this Ca(2+)-binding protein, which can regulate various Ca(2+)-dependent enzyme activations in liver cells. The regucalcin gene is localized on the X chromosome. Regucalcin plays a multifunctional role in cell regulation through maintaining intracellular Ca(2+) homeostasis and suppressing signal transduction in various cell types. The cytoplasmic regucalcin is translocated into the nucleus and inhibits nuclear Ca(2+)-dependent and -independent protein kinases and protein phosphatases, Ca(2+)-activated deoxyribonucleic acid (DNA) fragmentation and DNA and ribonucleic acid (RNA) synthesis. Moreover, overexpression of endogenous regucalcin regulates the gene expression of various proteins that are related to cell proliferation and apoptosis. This review will discuss the role of regucalcin in the regulation of cell nuclear function and an involvement in gene expression as a novel transcription factor.