Lysophosphatidic acid (LPA) and its receptors, LPA1-6, are integral parts of signaling pathways involved in cellular proliferation, migration and survival. These signaling pathways are of therapeutic interest for the treatment of multiple types of cancer and to reduce cancer metastasis and side effects. Validated therapeutic potential of key receptors, as well as recent structure-activity relationships yielding compounds with low nanomolar potencies are exciting recent advances in the field. Some compounds have proven efficacious in vivo against tumor proliferation and metastasis, bone cancer pain and the pulmonary fibrosis that can result as a side effect of pulmonary cancer radiation treatment. However, recent studies have identified that LPA contributes through multiple pathways to the development of chemotherapeutic resistance suggesting new applications for LPA antagonists in cancer treatment. This review summarizes the roles of LPA signaling in cancer pathophysiology and recent progress in the design and evaluation of LPA agonists and antagonists.