Lysophosphatidic acids (LPAs) are structurally simple lipid phosphate esters with a widely appreciated role as extracellular signaling molecules. LPA binds to selective cell surface receptors to promote cell growth, survival, motility and differentiation. Studies using LPA receptor knockout mice and experimental therapeutics targeting these receptors identify roles for LPA signaling in processes that include cardiovascular disease and function, angiogenesis, reproduction, cancer progression and neuropathic pain. These studies identify considerable functional redundancy between these receptors and raise the possibility that additional lysophosphatidic acid receptors remain to be identified. LPA is present in the blood and other biological fluids at physiologically relevant concentrations and can likely be rapidly generated and degraded in different locations, for example at sites of inflammation, vascular injury and thrombosis or in the tumor micro environment. Recent work identifies a secreted enzyme, autotaxin (ATX), as the key component of an extracellular pathway for generation of lysophosphatidic acid by lysophospholipase D catalyzed hydrolysis of lysophospholipid substrates. In contrast to the apparently redundant functions of LPA receptors, studies using ATX knock out and transgenic mice indicate that this enzyme is uniquely required for LPA signaling during early development and serves as the primary determinant of circulating LPA levels in adult animals. Accordingly, pharmacological inhibition of ATX may be a viable and potentially effective way to interfere with LPA signaling in the cardiovascular system and possibly other settings such as tumor metastasis for therapeutic benefit. In this review we provide an update on recent advances in defining roles for LPA signaling in major disease processes and discuss recent progress in understanding the regulation and function of autotaxin focusing on strategies for the identification and initial evaluation of small molecule autotaxin inhibitors.