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The WW domain-containing oxidoreductase gene (<i>WWOX</i>) was cloned 21 years ago as a putative tumor suppressor gene mapping to chromosomal fragile site FRA16D. The localization of <i>WWOX</i> in a chromosomal region frequently altered in human cancers has initiated multiple current studies to establish its role in this disease. All of this work suggests that WWOX, due to its ability to interact with a large number of partners, exerts its tumor suppressive activity through a wide variety of molecular actions that are mostly cell specific.