Autotaxin (ATX or ENPP2) is an ectonucleotide pyrophosphatase/phosphodiesterase (ENPP) that functions as a secreted lysophospholipase D to produce the multifunctional lipid mediator lysophosphatidic acid (LPA) from more complex lysophospholipids. LPA acts on distinct G protein-coupled receptors thereby activating multiple signaling cascades and cellular responses. The ATX-LPA signaling axis is implicated in a remarkably wide variety of physiological and pathological processes, ranging from vascular and neural development to lymphocyte homing, fibrosis and cancer. Despite much progress in understanding LPA receptor signaling, the precise mode of action of ATX has long remained elusive due to the lack of structural data. In particular, it has been unclear what makes ATX a unique lysophospholipase D and how the enzyme is targeted to LPA-responsive cells. Recent structural studies have begun to clarify these issues. Here we discuss new insights and inferences from the ATX structure.