Spectrin is the major constituent protein of the erythrocyte cytoskeleton which forms a filamentous network on the cytoplasmic face of the membrane by providing a scaffold for a variety of proteins. In this review, several aspects of spectrin organization are highlighted, particularly with respect to its ability to bind hydrophobic ligands and its interaction with membrane surfaces. The characteristic binding of the fluorescent hydrophobic probes Prodan and pyrene to spectrin, which allows an estimation of the polarity of the hydrophobic probe binding site, is illustrated. In addition, the contribution of uniquely localized and conserved tryptophan residues in the 'spectrin repeats' in these processes is discussed. A functional implication of the presence of hydrophobic binding sites in spectrin is its recently discovered chaperone-like activity. Interestingly, spectrin exhibits residual structural integrity even after denaturation which could be considered as a hallmark of cytoskeletal proteins. Future research could provide useful information about the possible role played by spectrin in cellular physiology in healthy and diseased states.