AbstractChanges in cellular Ca2+ concentrations form a ubiquitous signal regulating numerous processes such as fertilization, differentiation, proliferation, contraction, and secretion. The Ca2+ signal, highly organized in space and time, is generated by the cellular Ca2+ signaling toolkit. Lysophospholipids, such as sphingosine‐1‐phosphate (S1P), sphingosylphosphorylcholine (SPC), or lysophosphatidic acid (LPA) use this toolkit in a specific manner to initiate their cellular responses. Acting as agonists at G protein‐coupled receptors, S1P, SPC, and LPA increase the intracellular free Ca2+ concentration ([Ca2+]i) by using the classical, phospholipase C (PLC)‐dependent pathway as well as PLC‐independent pathways such as sphingosine kinase (SphK)/S1P. The S1P1 receptor, via protein kinase C, inhibits the [Ca2+]i transients caused by other receptors. Both S1P and SPC also act intracellularly to regulate [Ca2+]i. Intracellular S1P mobilizes Ca2+ in intact cells independently of G protein‐coupled S1P receptors, and Ca2+ signaling by many agonists requires SphK‐mediated S1P production. As shown for the FcεRI receptor, PLC and SphK may contribute specific components to the overall [Ca2+]i transient. Of the many open questions, identification of the intracellular S1P target site(s) appears to be of particular importance.