SL de novo biosynthesis can be simplified into three key steps: a gate-keeper and two cell fate modulator steps. The former comprises the up-stream rate-limiting step of the condensation of acyl-CoA and L-serine, in the endoplasmic reticulum (ER) via serine palmitoyltransferase (SPT), to produce dihydrosphingosine. The latter comprises first the formation of CER in the ER by the action of ceramide synthase (CerS), and then the formation of complex SLs in the Golgi. These products vary depending on the species, and are formed under the catalysis of what could be generically termed SL synthases: SM synthase in mammals and IPC synthase in fungi, plants and protozoa. It is worth mentioning that another Golgi localized metabolic pathway results in the formation of glycosylated CER species, and also contributes to the regulation CER levels (Holthuis & Menon, 2014) (Fig. 2).