Sphingosine-1-phosphate (SIP), a simple, bioactive sphingolipid metabolite, plays a key role, both intracellularly and extracellularly, in various cellular processes such as proliferation, survival, migration, inflammation, angiogenesis, and endothelial barrier integrity. The cellular S1P level is low and is tightly regulated by its synthesis and degradation. Sphingosine Kinases (SphKs) 1 and 2, catalyze the ATP-dependent phosphorylation of sphingosine to S1P, while the degradation is mediated by the reversible dephosphorylation catalyzed by the S1P phos-phatases and lipid phosphate phosphatases and the irreversible degradation to hexadecenal and ethanolamine phosphate by sphingosine-1-phosphate lyase (S1PL). As a ligand for specific G-protein-coupled receptors, S1P(1-5), which are differentially expressed in different cell types, S1P generates downstream signals that play crucial role in developmental and disease related pathologies. In addition to acting extracellularly on receptors located on the plasma membrane, S1P can also act intracellularly, independently of S1P(1-5), affecting calcium homeostasis and cell proliferation. The SphKs /S1P /S1PL metabolic pathway is implicated in numerous human pathologies including respiratory disorders, thereby raising the possibility that manipulating intracellular S1P levels could offer therapeutic potential in ameliorating lung diseases. This review focuses on the prospects of targeting S1P signaling and S1P metabolizing enzymes using small molecule inhibitors, receptor agonists, and antagonists in the treatment of lung diseases. (C) 2016 Elsevier Inc All rights reserved.