multiple stress stimuli such as ultraviolet (UV) and ionizing radiation, binding of death receptors and chemotherapeutic agents such as platinum, histone deacetylase inhibitors and paclitaxel. In some studies, SMase activation results to its transport to the plasma membrane and the simultaneous formation of ceramide. Ceramide transfer protein (CERT) transports ceramide from ER to the Golgi for the synthesis of SM. CERT is known to bind phosphatidylinositol phosphates, hinting its potential regulation via phosphorylation, a step of the ceramide metabolism that can be enzymatically regulated by protein kinases and phosphatases, and by inositol lipid metabolic pathways. Up to date, there are at least 26 distinct enzymes with varied subcellular localizations, that act on ceramide as either a substrate or product. Regulation of ceramide levels can therefore be performed by one of these enzymes in distinct organelles by particular mechanisms at various times. Sphingosine Sphingosine (Sph) is formed by the action of ceramidase (CDase) enzymes on ceramide in the lysosome. Sph can also be formed in the extracellular (outer leaflet) side of the plasma membrane by the action of neutral CDase enzyme. Sph then is either recycled back to ceramide or phosphorylated by one of the sphingosine kinase enzymes, SK1 and SK2. The product sphingosine-1-phosphate (S1P) can be dephosphorylated in the ER to regenerate sphingosine by certain S1P phosphatase enzymes within cells, where the salvaged Sph is recycled to ceramide. Sphingosine is a single-chain lipid (usually 18 carbons in length), rendering it to have sufficient solubility in water. This explains its ability to move between membranes and to flip-flop across a membrane. Estimates conducted at physiological pH show that approximately 70% of sphingosine remains in membranes while the remaining 30% is water-soluble. Sph that is formed has sufficient solubility in the liquid found inside cells (cytosol). Thus, Sph may come out of the lysosome and move to the ER without the need for transport via proteins or membrane-enclosed sacs called vesicles. However, its positive charge favors partitioning in lysosomes. It is proposed that the role of SK1 located near or in the lysosome is to ‘trap’ Sph via phosphorylation. It is important to note that since sphingosine exerts surfactant activity, it is one of the sphingolipids found at lowest cellular levels. The low levels of Sph and their increase in response to stimulation of cells, primarily by activation of ceramidase by growth-inducing proteins such as platelet-derived growth factor and insulin-like growth factor,