Lysophosphatidic acid and sphingosine 1-phosphate are bioactive lysophospholipids (LPLs) that transmit signals through a family of G-protein-couple receptors to control cellular differentiation and survival, as well as vital function of several types of immune cells. In addition, LPA and S1P are potent inducers of many of the hallmarks of cancer including cell proliferation, survival, migration, invasion and neovascularization. The enzymes that produce these two small lysophospholipids are aberrant in multiple cancer lineages and exhibit transforming activity. Additionally, LPLs levels are increased in patients with several types of cancer including melanoma. NK cells are critical members of the immunological tumor surveillance machinery. They are able to attack abnormal cells such as virus-infected cells or transformed tumor cells. Enhanced NK cell cytotoxic activity after stimulation with classical chemotaxins such as RANTES/CCL5 is well known. These classical chemotaxins bind to specific Gi protein-coupled receptors linked to activation of phospholipase C and PIP3–generating type IB phosphatidylinositol 3-kinase. Moreover, LPA and S1P induce chemotaxis of NK cells through pertussis toxin sensitive-G proteins. In this context, the biological functions of LPLs and their influence on the interaction of human NK cells with tumor cells were characterized.