1. Oscillatory increases in the cytoplasmic Ca(2+) concentration ([Ca(2+)](cyt)) play essential roles in the hormonal regulation of liver cells. Increases in [Ca(2+)](cyt) require Ca(2+) release from the endoplasmic reticulum (ER) and Ca(2+) entry across the plasma membrane. 2. Store-operated Ca(2+) channels (SOCs), activated by a decrease in Ca(2+) in the ER lumen, are responsible for maintaining adequate ER Ca(2+). Experiments using patch-clamp recording and the fluorescent Ca(2+) reporter fura-2 indicate there is only one type of SOC in rat liver cells. These SOCs have a high selectivity for Ca(2+) and properties essentially indistinguishable from those of Ca(2+) release-activated Ca(2+) (CRAC) channels. 3. Although Orai1, a CRAC channel pore protein, and stromal interaction molecule 1 (STIM1), a CRAC channel Ca(2+) sensor, are components of liver cell SOCs, the mechanism of activation of SOCs, and in particular the role of subregions of the ER, are not well understood. 4. Recent experiments have used the transient receptor potential vanilloid 1 (TRPV1) non-selective cation channel, ectopically expressed in liver cells, and a choleretic bile acid to deplete Ca(2+) from different ER subregions. The results of these studies have provided evidence that only a small component of the ER is required for STIM1 redistribution and the activation of SOCs. 5. It is concluded that different Ca(2+) microdomains in the ER and cytoplasmic space are important in both the activation of SOCs and in the signalling actions of Ca(2+) in liver cells. Future experiments will investigate the nature of these microdomains further.