Tetraspanin KAI1/CD82 is a wide-spectrum tumor metastasis suppressor. KAI1/CD82 suppresses tumor metastasis by primarily inhibiting cancer cell motility and invasiveness. In tetraspanin-enriched microdomain, KAI1/CD82 associates with the proteins important for cell migration such as cell adhesion molecule, growth factor receptor, and signaling molecule. Likely, KAI1/CD82 down-regulates the functions of these motility-related proteins to inhibit cell migration. The loss of KAI1/CD82 expression in invasive and metastatic cancers is due to a complex, epigenetic mechanism that probably involves transcription factors such as NFkappaB, p53, and beta-catenin.