Identified as a tyrosine phosphorylated protein in Rous sarcoma virus-transformed chick embryo fibroblasts (CEF), caveolin is now known to be ubiquitously expressed. Caveolin (also known as VIP21) localizes to non-clathrin membrane invaginations (caveolae) on the inner surface of the plasma membrane. This transmembrane protein plays a structural role in these specializations. Caveolin is also present at the trans-Golgi network (TGN) and similar quantities are found in apically and basolaterally destined transport vesicles. Caveolin-1 is present in two forms, α and β, due to alternate splicing of the mRNA. The α isoform has been reported to be observed at 24 kD and the β isoform at 21 kD. During caveolae formation, caveolin-1 forms large lipid-binding homo-oligomers. In addition, phosphorylation of caveolin at Tyr-14, Ser-88, and other residues in v-src transformed cells leads to flattening, aggregation, and fusion of caveolae and caveolae-derived vesicles. Caveolin-1 may also function as a scaffolding protein, which organizes signaling molecules. This functional role is supported by the fact that caveolin-1 interacts directly with inactive ras and G-protein α subunits. Although caveolin 2 is similar to caveolin 1 in distribution and tissue expression, caveolin 2 is most abundant in adipose tissue and its expression is up-regulated upon differentiation. Caveolin 3 has been identified as a distinct isoform which is expressed only in smooth, skeletal, and cardiac muscle. Flotillin-1 was also isolated from the Triton X-100 insoluble buoyant fraction that includes caveolae. Although the mRNA expression of both flotillin-1 and Caveolin is very similar, caveolin is undetectable in brain, while flotillin-1 is very abundant. Flotillin-1 is a close homolog of the Epidermal Surface Antigen (ESA/flotillin-2), which also colocalizes in the caveolae. Thus, flotillin-1 and its relative ESA/flotillin-2 are also incorporated into the expanding list of proteins co-localized with caveolae, which includes PKCα, Ras, Rap Src-like kinases, Gαβγ, GPI-linked receptors and Nitric Oxide Synthases.