Simple SummaryProstate cancer (PC) is the most common cancer in men over 65 and the fifth leading cause of death by cancer in men. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that regulates cell proliferation, survival, differentiation, cell cycle, and apoptosis. S1P content and S1P-transforming enzymes activities are deregulated in several diseases including obesity, diabetes, neurological and cardiovascular disorders, and especially cancer. The implication of S1P metabolism in PC has been explored over the last 20 years in several in vitro and in vivo models of PC. Here we summarized (i) the most important findings about the role of S1P metabolism and its members in the oncogenesis of PC; and (ii) the most efficient molecules targeting S1P metabolism under preclinical and clinical development for curing PC.AbstractProstate cancer (PC) is the second most common cancer in men worldwide. More than 65% of men diagnosed with PC are above 65. Patients with localized PC show high long-term survival, however with the disease progression into a metastatic form, it becomes incurable, even after strong radio- and/or chemotherapy. Sphingosine 1-phosphate (S1P) is a bioactive lipid that participates in all the steps of oncogenesis including tumor cell proliferation, survival, migration, invasion, and metastatic spread. The S1P-producing enzymes sphingosine kinases 1 and 2 (SK1 and SK2), and the S1P degrading enzyme S1P lyase (SPL), have been shown to be highly implicated in the onset, development, and therapy resistance of PC during the last 20 years. In this review, the most important studies demonstrating the role of S1P and S1P metabolic partners in PC are discussed. The different in vitro, ex vivo, and in vivo models of PC that were used to demonstrate the implication of S1P metabolism are especially highlighted. Furthermore, the most efficient molecules targeting S1P metabolism that are under preclinical and clinical development for curing PC are summarized. Finally, the possibility of targeting S1P metabolism alone or combined with other therapies in the foreseeable future as an alternative option for PC patients is discussed. Research Strategy: PubMed from INSB was used for article research. First, key words “prostate & sphingosine” were used and 144 articles were found. We also realized other combinations of key words as “prostate cancer bone metastasis” and “prostate cancer treatment”. We used the most recent reviews to illustrate prostate cancer topic and sphingolipid metabolism overview topic.