In cells of the immune system, calcium signals are essential for diverse cellular functions including differentiation, effector function, and gene transcription. After the engagement of immunoreceptors such as T-cell and B-cell antigen receptors and the Fc receptors on mast cells and NK cells, the intracellular concentration of calcium ions is increased through the sequential operation of two interdependent processes: depletion of endoplasmic reticulum Ca(2+) stores as a result of binding of inositol trisphosphate (IP(3)) to IP(3) receptors, followed by 'store-operated' Ca(2+) entry through plasma membrane Ca(2+) channels. In lymphocytes, mast cells and other immune cell types, store-operated Ca(2+) entry through specialized Ca(2+) release-activated calcium (CRAC) channels constitutes the major pathway of intracellular Ca(2+) increase. A recent breakthrough in our understanding of CRAC channel function is the identification of stromal interaction molecule (STIM) and ORAI, two essential regulators of CRAC channel function. This review focuses on the signaling pathways upstream and downstream of Ca(2+) influx (the STIM/ORAI and calcineurin/NFAT pathways, respectively).