Human tetraspanin proteins are a group of 33 highly hydrophobic membrane proteins that can form complexes in cholesterol‐rich microdomains, distinct from lipid rafts, on the cell surface in a dynamic and reversible way. These complexes are composed of a core of several tetraspanin proteins that organize other membrane proteins such as integrins, human leukocyte antigen (HLA) antigens and some growth factor receptors. Although most tetraspanin proteins have been studied individually, tetraspanin proteins and their complexes can have effects on cellular adhesion and motility, interactions with stroma or affect signaling by growth factors, and for most of them no ligand has been identified. Functionally these proteins have been mostly studied in cells of lymphoid lineage, but they are present in all cell types. Data is also available for some tumors, where some tetraspanins have been identified as metastasis suppressors, but their significance is still not clear. Some of their implications in tumor biology and the areas that deserve further study are outlined. (Cancer Sci 2007; 98: 1666–1677)