Significance Sphingolipids (SLs) are complex lipids that constitute hundreds of subspecies. All SLs share a long-chain base (LCB) as a defining structural component. LCBs are formed by serine-palmitoyltransferase (SPT) in the first and rate-limiting step of SL de novo synthesis. SPT consists of three subunits that show tissue-specific expression. In presence of the SPTLC3 subunit, the enzyme forms a spectrum of straight and branched LCBs with distinct biochemical and biophysical properties. This alters the composition of cellular membranes and might influence the dynamics of membrane-related transport and signaling events. SPTLC3 is particularly abundant in skin, and changes in SPT activity are related to dermal pathologies. Genetic variants of SPTLC3 are associated with metabolic conditions such as dyslipidemia and atherosclerosis.