Many hormones, growth factors, and neurotransmitters stimulate their target cells by promoting the hydrolysis of plasma-membrane phosphoinositides to form the two second messengers, diacylglycerol and inositol 1,4,5-trisphosphate [Ins(1,4,5)P3]. In such cells, ligand-receptor interaction stimulates specific phospholipases that are activated by guanyl nucleotide regulatory G proteins or tyrosine phosphorylation. In many cells, the initial rise in cytoplasmic calcium due to Ins(1,4,5)P3-induced mobilization of calcium from agonist-sensitive stores is followed by a sustained phase of cytoplasmic calcium elevation that maintains the target-cell response, and is dependent on influx of extracellular calcium. Numerous inositol phosphates are formed during metabolism of the calcium-mobilizing messenger, inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], to lower and higher phosphorylated derivatives. The cloning of several phospholipase-C isozymes, as well as the Ins(1,4,5)P3-5 kinase and the Ins(1,4,5)P3 receptor, have clarified several aspects of the diversity and complexity of the phosphoinositide-calcium signaling system. In addition to their well-established roles in hormonal activation of cellular responses such as secretion and contraction, phospholipids and their hydrolysis products have been increasingly implicated in the actions of growth factors and oncogenes on cellular growth and proliferation.