Endothelins (ET) are a family of regulatory peptides synthesized by selected endothelial and epithelial cells that act in a paracrine fashion on nearby smooth muscle or connective tissue cells. We review the pathways of transmembrane signaling triggered by binding of endothelin peptides to receptors on the plasma membrane. Although our understanding of many components is unclear, endothelin peptides appear to evoke a phosphoinositide-linked signaling system that bears a striking resemblance to signaling pathways activated by other regulatory peptides. Expression of endothelin receptors and specific pathways stimulated by activated receptors are controlled in a cell- and tissue-specific manner, which perhaps explains the diverse biological actions of endothelin in different tissues. Complex negative feedback pathways regulate endothelin-induced signaling at the receptor and second messenger levels. Moreover, by regulating the activity of sequence-specific DNA binding proteins, short-term signals by ET can be extended to long-term effects involving gene expression. Regulation of gene expression by ET could account for complex events such as mitogenesis and vascular and tissue remodeling in disease.— Simonson, M. S.; Dunn, M. J. Cellular signaling by peptides of the endothelin gene family. FASEB J. 4: 2989-3000; 1990.