Sphingosine-1-phosphate (S1P) was first identified as a lysophospholipid metabolite whose formation is required for the irreversible degradation of sphingolipids. Years later, it was discovered that S1P is a bioactive lipid that provokes varied cell responses by acting through cell-surface receptors to drive cell signaling. More recent findings in model organisms have now established that S1P metabolism and signaling are integrated into many physiological systems. We describe here the surprising breadth of function of S1P in mammalian development and the underlying biologic processes that S1P regulates.