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This article is available online at http://www.jlr.org differentiation, and intracellular traffi cking ( 1 ). It has been demonstrated that cells adjust SL production in response to metabolic needs ( 2 ). SM is biochemically synthesized through the activity of serine-palmitoyl-CoA transferase, 3-ketosphinganine reductase, ceramide (Cer) synthase, dihydroceramide desaturase, and sphingomyelin synthase (SMS). SMS, which uses Cer and phosphatidylcholine as substrates, is the last enzyme in SM biosynthesis ( 3 ). Two isoforms, SMS1 and SMS2, have been cloned in mammals ( 4 ). SMS1 localizes in the Golgi apparatus, whereas SMS2 can be localized in the PM ( 5 ) but also in the Golgi apparatus. Although SM is principally synthesized by SMS1 activity, it has been reported that both SMS1 and SMS2 are required for SM homeostasis and growth in human HeLa cells ( 6 ). SM synthesis is directly related to correct intracellular protein traffi cking ( 7 ). It has been recently shown that the downregulation of SMSs significantly retards the traffi cking of the reporter protein vesicular stomatitis virus G protein tagged with GFP from the trans-Golgi network to the PM. Moreover, the correct endosomal recycling network is directly related to Golgi SM synthesis ( 8 ).SM is the main SL in mammalian cells. Because of the high affi nity of interaction with cholesterol, SM drives the formation of PM rafts or detergent-resistant microdomains (DRMs) ( 9, 10 ), thus providing a framework for PM organization. Early studies have demonstrated