Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are bioactive lysophospholipid mediators with a wide variety of biological actions. G-protein-coupled receptors for LPA and S1P have been identified, and physiological and pathological significances of the lysophospholipids and their receptors are under intensive investigation. Furthermore, specific agonists and antagonists for the receptors have been developed for clinical applications. However, mechanisms underlying their production have not yet been fully elucidated. Recently, autotaxin, an exo-phosphodiesterase implicated in tumor cell migration, has been discovered as lysophospholipase D that produces LPA and S1P from lysophosphatidylcholine and sphingosylphosphorylcholine, respectively. In this article, I reviewed the structure, expression, substrate specificity, enzymatic function, specific inhibitors and pathophysiological significances of lysophospholipase D/autotaxin.