SNAREs are small, mostly membrane associated proteins that are essential for all intracellular membrane fusion steps (except for mitochondrial fusion). SNAREs share as a common feature a conserved stretch of 60-70 aa, the so called SNARE-motif. For each fusion step, a specific set of SNARE proteins is required. For instance, in regulated exocytosis the neuronal SNAREs syntaxin 1A and SNAP-25 at the plasma membrane form a complex with synaptobrevin 2 at the vesicle membrane, leading to fusion of the opposed membranes. In 2001 two groups independently from each other found evidence that the neuronal SNAREs are not uniformly distributed but spatially organized. Chamberlain et al. tested if SNAREs co-float with membrane raft domain markers. At that time, proteins were defined to be associated with membrane rafts when they enriched in so-called detergent resistant membranes (DRMs). After cell solubilisation, DRMs can be readily isolated from lysed cells by density gradient centrifugation: As they are composed of proteins and associated lipids, they are of lower density than e.g. cytosolic proteins and float up to lower densities during gradient centrifugation. Chamberlain et al. showed that indeed a fraction of the neuronal SNAREs co-floated with detergent resistant membrane markers. It was also shown that the protein is not floating after cholesterol depletion, consistent with the idea of raft association and documenting that cholesterol is important for the spatial organisation of SNAREs. Interestingly, block of cholesterol synthesis by lovastatin led to a block in exocytotic activity indicating that raft association is of functional importance. At the same time a microscopic analysis of the spatial distribution of syntaxin 1 in plasma membrane sheets showed that syntaxin 1 was concentrated in cholesterol-dependent clusters that defined docking and fusion sites for exocytosis (Lang et al., 2001). Evidence for cholesterol association was provided by photolabeling of synatxin by photoactivatable cholesterol. Cholesterol depletion led to disintegration of syntaxin clusters and to a loss of exocytosis. Hence, both studies in principle provided evidence for the idea that SNAREs form plasmalemmal stuctures that depend on cholesterol and are important for exocytosis. However, the DRMs isolated by Lang et al. were devoid of SNAREs. Additionally it was shown on membrane sheets that syntaxin clusters did not overlap with raft markers (see also Ohara-Imaizumi et al., 2004). These conflicting results led to a disagreement regarding the interpretation of the nature of these structures, which from then on were called rafts by some groups and clusters by others. The controversy went on as in the following years DRMs were prepared also from other cell types, and depending on how stringent the solubilization criteria were applied, SNAREs were partially associated with or not present in DRMs. When investigated in model membranes, SNAREs were usually found to prefer the disorderd (non-raft) phase. However, despite of the controversy if SNAREs are associated with rafts, it is undebated that they form plasmalemmal structures that are important for membrane fusion, and the different affinities of SNAP-25 and SNAP-23 (involved in constitutive exocytosis) to rafts may even fine tune the different exocytotic pathways in which these proteins operate (Salaun et al., 2005). In any case, a recent new definition of rafts will probably make the debate on DRMs association less crucial. On the Keystone Symposim on ‘Lipid rafts and cell function’ membrane rafts have now been defined (Pike L.J. (2006). J. Lipid Res. 47, 1597-1598) to be ‘small (10–200 nm), heterogeneous, highly dynamic, sterol- and sphingolipid-enriched domains that compartmentalize cellular processes. Small rafts can sometimes be stabilized to form larger platforms through protein-protein and protein-lipid interactions.’ Interestingly, the ‘raftologists’ have disregarded detergent resistance as criteria for raft association. According to this new definition, all characteristics so far determined for SNAREs fulfill the raft criteria: they contain cholesterol, compartmentalize cellular dynamics, and a recent study (Sieber et al., 2006) has shown that their size is in the required range. Hence, it may turn out in the future that SNAREs are bona fide membrane rafts.