Sphingolipids such as sphingomyelin (SM) are important components of cellular membranes and dynamic regulators of a wide range of cellular processes in most organisms. Ceramides constitute the backbone of all sphingolipids and are synthesised on the cytosolic surface of the endoplasmic reticulum (ER) then transported to the Golgi for conversion to SM. The ER-membrane resident protein sphingomyelin synthase-related protein 1 (SAMD8) catalyses the synthesis of the SM analogue ceramide phosphoethanolamine (CPE) in the ER lumen. SAMD8 only produces trace amounts of CPE but blocking its catalytic activity causes a substantial rise in ER ceramide levels and a structural collapse of the early secretory pathway. SAMD8 is therefore a key regulator of ceramide homeostasis, functioning as a sensor rather than a converter of ceramides in the ER (Vacaru et al. 2009).