Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are naturally arising bioactive lipids. The roles of LPA and S1P in angiogenesis, tumor growth and metastasis have recently emerged. Blood platelets are an important source of LPA and S1P in the organism. However, other types of cells including cancer cells expressing autotaxin and sphingosine kinases have the capacity to produce LPA and S1P, respectively. During the past decade, studies revealed that LPA and S1P interact with a large series of G-protein-coupled receptors, at least seven for LPA (LPA1-5, GPR-87, P2Y5) and five for S1P (S1P1-5). This may account for the wide variety of cell types reacting to LPA and S1P stimulation and for the wide range of cellular functions controlled by these lysophospholipids such as proliferation, survival and motility. Genetic and pharmacological approaches were developed to block the activities of LPA or S1P in the context of cancer progression. This article presents recent findings based on extensive cell culture experiments and preliminary in vivo studies which demonstrate that targeting the lysophospholipid tracks would be extremely beneficial for patients suffering from cancer.