Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are potent biologically active lipid mediators that exert a wide range of cellular effects through specific G protein-coupled receptors. To date, four LPA receptors and five S1P receptors have been identified. These receptors are expressed in a large number of tissues and cell types, allowing for a wide variety of cellular responses to lysophospholipid signaling, including cell adhesion, cell motility, cytoskeletal changes, proliferation, angiogenesis, process retraction, and cell survival. In addition, recent studies in mice show that specific lysophospholipid receptors are required for proper cardiovascular, immune, respiratory, and reproductive system development and function. Lysophospholipid receptors may also have specific roles in cancer and other diseases. This review will cover identification and expression of the lysophospholipid receptors, as well as receptor signaling properties and function. Additionally, phenotypes of mice deficient for specific lysophospholipid receptors will be discussed to demonstrate how these animals have furthered our understanding of the role lysophospholipids play in normal biology and disease.