Sphingosine 1-phosphate (S1P) is a sphingolipid metabolite that regulates diverse biological functions. S1P has been identified as a high-affinity ligand for a family of five G-protein-coupled receptors, known as the S1P receptors. The physiological role of the S1P receptor S1P(1) in vascular maturation was recently revealed by gene disruption in mice. In addition to other cellular processes, the binding of S1P to its receptors regulates motility and directional migration of a variety of cell types, including endothelial cells and vascular smooth muscle cells. This review focuses on the important role of S1P and its receptors in cell migration and describes a new paradigm for receptor cross-communication in which transactivation of S1P(1) by a receptor tyrosine kinase (PDGFR) is crucial for cell motility.