Lysophosphatidic acid (LPA) is a bioactive phospholipid that signals through G-protein-coupled receptors to produce a range of biological responses. A recently reported LPA receptor GPR23 (LPA4 receptor) has a low homology to the LPA(1-3) receptors identified previously. In Chinese hamster ovary cells expressing the human GPR23, LPA induced an increase in cellular cyclic adenosine monophosphate (cAMP) and calcium levels. GPR23-selective agonists or antagonists have not been reported previously. Such ligands, if available, would be valuable tools for studying the functions of this receptor. Here we report the identification of novel GPR23 agonists, inverse agonists, and a negative modulator from 2 high-throughput screens, a beta-lactamase reporter screen, and a [3H]LPA-binding screen. Several screening hits were selected for mechanism of action studies using the beta-lactamase reporter assay and a cAMP assay. An evaluation of their selectivity at the other LPA receptors was also conducted. This study demonstrates a strategy for the identification of GPR23 agonists and inverse agonists. We believe the strategy employed here is applicable to other constitutively active GPCRs.