The unique structural features of SLs (the free 3-hydroxy group, the amide functionality and the C4–C5 trans double bond) affect their biophysical properties rendering these molecules different from their glycerolipid counterparts, i.e. SM vs phosphatidylcholine (PC) (Boggs, 1980, 1987; Talbott et al., 2000; Ramstedt & Slotte, 2002). Such interfacial differences give complex SLs, such as SM, the unique ability to form both intra- and intermolecular hydrogen bonds (Bruzik, 1988) that are fine-tuned by the trans double bond (Ramstedt & Slotte, 2002). This ability is reflected in the tendency of SLs to cluster rather than behave like typical ‘fluid’ membrane lipids. Naturally occurring SLs undergo the Lβ (gel phase) to Lα (lamellar phase) transition near the physiological temperature of 37 °C, in contrast, this transition for naturally occurring glycerolipids is near or below 0 °C. Additionally, the long saturated alkyl chains of SLs allow them to pack tightly with sterols, stabilized by hydrogen bonding (Ramstedt & Slotte, 2002), to form laterally compact hydrophobic micro-domains commonly known as ‘lipid rafts’ (Futerman & Hannun, 2004). Similar results have been reported with the fungal/plant counterpart of SM, IPC, where it was shown that IPC was able to form sterol containing ordered domains in model systems (Björkbom et al. 2010). These membrane micro-domains can readily segregate from the more disordered and expanded domains of unsaturated acyl chains of glycerolipids (Merrill & Sandhoff, 2002). They have been proposed to function in a diverse array of processes from polarised trafficking of lipid modified proteins (Brown & London, 1998) and the stabilization of other types of biological structures such as lamellar bodies, to the assembly and activation of signal transduction complexes (Brown & London, 2000; Magee et al. 2002; Pierce, 2002; Vance & Vance, 2002; Hannun & Obeid, 2008). They have also been involved in the formation of detergent-insoluble gel-phase domains (Ramstedt & Slotte, 2002) via the extensive hydrogen-bonding network in the head groups of GSLs that have been implicated during the formation of ‘caveolae’ and surface recognition (Merrill & Sandhoff, 2002).