Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are serum-borne lysophospholipids that signal through their cognate G protein-coupled receptors to evoke a great variety of responses in numerous cell types. In addition to stimulating cell proliferation and survival, LPA and S1P induce profound cytoskeletal changes through Rho-mediated signaling pathways, leading to such diverse responses as cell rounding, neurite retraction, and modulation of tumor cell invasiveness (transcellular migration). A major recent advance is the identification of a subfamily of heptahelical receptors for LPA and S1P.