Sphingosine-1-phosphate (S1P) is now recognized as a lipid mediator that acts via G-protein-coupled receptors. S1P receptors couple to various heterotrimeric G-proteins and regulate downstream targets and ultimately cell behaviour. The prototypical S1P1 receptor is known to couple to Gi and regulates angiogenesis, vascular development, and immune cell trafficking. In this review, we focus our attention on the S1P2 receptor, which has a unique G-protein-coupling property in that it preferentially activates the G(12/13) pathway. Recent studies indicate that the S1P2 receptor regulates critical intracellular signalling pathways, such as Rho GTPase, the phosphatase PTEN, and VE-cadherin-based adherens junctions. Analysis of mutant mice has revealed the critical role of this receptor in inner ear physiology, heart and vascular development, vascular remodelling, and vascular tone, permeability, and angiogenesis in vertebrates. These studies suggest that selective modulation of S1P2 receptor function by pharmacological tools may be useful in a variety of pathological conditions.