Glycosphingolipids aggregate with sphingomyelin and cholesterol in the outer leaflet of the plasma membranes to become included in transmembrane domains comprising saturated phospholipids in the inner leaflet, select transmembrane proteins and acylated proteins anchored to the cytofacial aspect. Such domains constitute liquid-ordered, planar and short-lived rafts, floating in the liquid-disordered glycerophospholipid medium of the membrane outer leaflet. When scaffolded by the protein caveolin, such rafts assume the shape of microscopically detectable small invaginations or caveolae. Rafts and caveolae are plasma membrane microdomains involved in membrane trafficking, endocytosis, transcytosis, signal transduction and adhesion, and may be opportunistically utilized by various microbial pathogens to enter many different types of host cells. By virtue of the greater cohesion of their sphingolipid and cholesterol components, rafts and caveolae constitute stable membrane platforms that associate receptors, kinases, phosphatases and adaptor proteins, and promote their interactions in a membrane environment conducive to optimal signaling. Such membrane platforms are involved in a variety of cellular interactions with extracellular matrices, cells, microbes and soluble ligands. The capacity of protein receptors to associate with or dissociate from rafts is in part due to the affinity of their “lipid shells” for the sphingolipid aggregates, as well as to their extramembranous properties and characteristics. In particular, carbohydrate side-chains of N-glycosylated receptors may interact with gangliosides in rafts and then change the conformation, affinity and signaling properties of the glycoprotein receptors. Rafts and caveolae are targeted in several therapeutic approaches aiming at modifying their contents and function. Such approaches have been applied successfully to the treatment of cancer cells and of cells unresponsive to physiological insulin triggering.