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Caveolae and lipid rafts are two distinct populations of free cholesterol, sphingolipid (FC/SPH)-rich cell surface microdomains. They differ in stability, shape, and the presence or absence of caveolin (present in caveolae) or GPI-anchored proteins (enriched in lipid rafts). In primary cells, caveolae and rafts support the assembly of different signaling complexes, though signal transduction from both is strongly dependent on the presence of FC. It was initially thought that FC promoted the formation of inactive reservoirs of signaling proteins. Recent data supports the concept of a more dynamic role for FC in caveolae and probably, also lipid rafts. It is more likely that the FC content of these domains is actively modulated as protein complexes are formed and, following signal transduction, disassembled. In transformed cell lines with few caveolae, little caveolin and a preponderance of rafts, complexes normally assembled on caveolae may function in rafts, albeit with altered kinetics. However, caveolae and lipid rafts appear not to be interconvertible. The presence of non-caveolar pools of caveolin in recycling endosomes (RE), the trans-Golgi network (TGN) and in mobile chaperone complexes is now recognized. A role in the uptake of microorganisms by cells ascribed to caveolae now seems more likely to be mediated by cell surface rafts.