The lipid mediator lysophosphatidic acid (LPA) was first identified more than thirty years ago as an agent regulating multiple physiological responses including platelet aggregation, blood pressure, contraction of smooth muscle cells, cell shape, and neurite outgrowth. In the last two decades, discoveries of autotaxin (ATX)—the major LPA-producing lysophospholipase D enzyme—and the family of six LPA G protein coupled receptors (GPCR, namely LPAR1–6) with omnipresent roles in malignancies from cell transformation, proliferation, invasion, and metastasis to survival against genotoxic or metabolic stress, rapidly propelled LPA to the center stage of cancer research. These observations collectively suggest that cancer cells have hijacked LPA to enhance tumor progression, metastasis, and therapy resistance. In spite of this, one major question remains: why are there no drug candidates targeting the ATXLPAR axis approved for the treatment of cancer? To address this question, we need to first understand the two major challenges in cancer treatment—therapy resistance and the impact of the tumor microenvironment (TME) on cancer progression and therapeutic response.