INTRACELLULAR Ca²⁺ signals that last more than a few minutes after the onset of stimulation depend critically on influx of extracellular Ca²⁺. Such Ca²⁺ influx can be triggered in many cell types by depletion of intracellular Ca²⁺ stores without detectable elevations of known messengers. The mechanism by which store depletion can control plasma membrane Ca^{2 +} permeability remains controversial^1–7. Here we present evidence for a novel soluble mediator. Calcium depletion of a lymphocyte cell line caused the messenger to be released from intracellular organelles into the cytoplasm and to a much lesser extent into the extracellular medium. The messenger caused Ca²⁺ influx when applied to macrophages, astrocytoma cells, and flbroblasts and was therefore named CIF (for Ca²⁺-influx factor). CIF appears to have hydroxyls (or hydroxyl and amino groups) on adjacent carbons, a phosphate, and a M_r under 500.