AbstractThe WW domain‐containing oxidoreductase (WWOX) spans one of the most active common fragile sites (CFSs) involved in cancer, FRA16D. WWOX encodes a 46‐kDa protein that contains two N‐terminal WW domains and a central short‐chain dehydrogenase/reductase (SDR) domain. Through its WW domain, Wwox interacts with its partners and modulates their functions. Our data indicate that Wwox suppresses the transactivation function of several transcription factors implied in neoplasia by sequestering them in the cytoplasm. Work from our laboratory and other research groups have demonstrated that Wwox participates in a number of cellular processes including growth, differentiation, apoptosis, and tumor suppression. Targeted deletion of the Wwox gene in mice causes increased spontaneous and chemically induced tumor incidence supporting bona fide tumor suppressor function of WWOX. Moreover, generation of the Wwox‐deficient mice uncovers, at least in part, some of the physiological in vivo functions of the WWOX gene. This review focuses on recent progress that elucidates Wwox functions in biology and pathology. J. Cell. Biochem. 108: 737–745, 2009. © 2009 Wiley‐Liss, Inc.