Tetraspanins are a large superfamily of cell surface membrane proteins characterised by their four transmembrane domains. They are expressed in a wide variety of cell types and have functional roles in processes, such as cellular adhesion, motility, activation and tumour invasion. Leukocytes express </=20 tetraspanin proteins on their surface. Tetraspanins have an exceptional ability to interact with a diverse array of important proteins, such as integrins, immunoreceptors and signalling molecules. They are thought to organise a novel type of cell surface membrane microdomain, which in leukocytes functions to regulate activation, motility and antigen presentation. The importance of tetraspanin microdomains in immunity is highlighted by the perturbations in the immune system observed in tetraspanin-deficient mice.