The WW domain-containing oxidoreductase (WWOX) gene is located at 16q23.1-16q23.2, a region that spans the second most common human fragile site, FRA16D. The WWOX protein contains two N-terminal WW domains and a central short chain oxidoreductase-like domain. In the last few years, considerable amount of data have shown inactivation of WWOX in a variety of human malignancies. Moreover, interacting partners have been identified biochemically that define, at least in part, the molecular mechanism of WWOX action. Recently, we demonstrated that targeted deletion of the Wwox gene in the mouse led to increased incidence of spontaneous and chemically induced tumor formation, thereby providing the first in vivo evidence that WWOX is a bona fide tumor suppressor. This review focuses on the most recent progress in understanding WWOX function as a tumor suppressor.