Regulation of free cytosolic Ca2+ level in the liver is important because of the many Ca2(+)-dependent processes in the liver, such as respiration, gluconeogenesis, glycogenolysis, cell division, etc. Free cytosolic Ca2+ levels are maintained in the unstimulated state below 1 microM. This level is maintained by an outwardly directed Ca2(+)-ATPase in the plasma membrane, sequestration into the endoplasmic reticulum by a Ca2(+)-ATPase, binding of Ca2+ to specific Ca2(+)-binding proteins, such as calmodulin, and membrane potential-driven uptake into the mitochondria. Upon stimulation by hormones which act by increasing cytosolic free Ca2+ levels, both Ca2+ influx and the release of stored Ca2+ from the endoplasmic reticulum contribute to the increases in cytosolic free Ca2+ levels. The exact mechanism(s) by which these events occur is being intensively studied and debated. Here, it is suggested that hormones activate through a second messenger 1) a ligand-gated Ca2+ channel present in the plasma membrane, and 2) a different Ca2+ channel present in the endoplasmic reticulum. As a result, cytosolic-free Ca2+ levels increase and Ca2(+)-dependent processes are activated. A role for the cytoskeleton in the activation of the ryanodine-binding channel is proposed. Future studies are needed to identify the molecular identity of the hepatic ryanodine receptor and to define the role of the cytoskeleton in signal transduction.