Ample evidence indicates that sphingosine-1-phosphate (SPP) can serve as an intracellular second messenger regulating calcium mobilization, cell growth, and survival. Moreover, the dynamic balance between levels of the sphingolipids metabolites, ceramide, and SPP, and consequent regulation of opposing signaling pathways, is an important factor that determines whether a cell survives or dies. This ceramide/SPP rheostat is an evolutionarily conserved stress regulatory mechanism influencing growth and survival of yeast. In addition, SPP also has been identified as the ligand for the G-protein-coupled receptors EDG-1, -3, -5, and -6. Binding of SPP to EDG-1 regulates chemotaxis and in vitro angiogenesis of endothelial cells, whereas EDG-5, and possibly EDG-3, are likely the cell surface receptors responsible for cell rounding and neurite retractions induced by SPP. Hence, the studies identify a family of highly specific SPP receptors that are capable of mediating different biological responses. Thus, it is suggested that SPP is a prototype for a novel class of lipid mediators that act both extracellularly as ligands for cell surface receptors and intracellularly as second messengers. Recently, sphingosine kinase was purified to homogeneity and the first mammalian sphingosine kinase, the enzyme responsible for the formation of SPP, was cloned. The studies should provide the necessary tools to develop insight into the biological roles of this important bioactive sphingolipid.