Intracellular free Ca(2+) ([Ca(2+)]i) is a highly versatile second messenger that regulates a wide range of functions in every type of cell and tissue. To achieve this versatility, the Ca(2+) signaling system operates in a variety of ways to regulate cellular processes that function over a wide dynamic range. This is particularly well exemplified for Ca(2+) signals in the liver, which modulate diverse and specialized functions such as bile secretion, glucose metabolism, cell proliferation, and apoptosis. These Ca(2+) signals are organized to control distinct cellular processes through tight spatial and temporal coordination of [Ca(2+)]i signals, both within and between cells. This article will review the machinery responsible for the formation of Ca(2+) signals in the liver, the types of subcellular, cellular, and intercellular signals that occur, the physiological role of Ca(2+) signaling in the liver, and the role of Ca(2+) signaling in liver disease.