Tetraspanins compose a family of structurally related molecules with four transmembrane domains. A total of 33 tetraspanins are present in the human genome, and tetraspanins are also found in plants and certain fungi. A well-known property of tetraspanins is their ability to interact with one another and many other surface proteins, which led to the suggestion that they organize a network of molecular interaction referred to as the 'tetraspanin web', and that they play a role in membrane compartmentalization. Recent studies of the dynamics of these molecules provided important new information that helped refining the models of this 'web'. Several genetic studies in mammals and invertebrates have demonstrated key physiological roles for some of the tetraspanins, in particular in immune response, sperm-egg fusion, photoreceptor function and the normal function of certain epitheliums or vascular development. However, in several examples, the phenotypes of tetraspanin-knockout mice are relatively mild or restricted to a particular organ, despite a wide tissue distribution.