Allelic imbalances affecting the long arm of chromosome 16 have been extensively reported in the literature as common abnormalities observed in various carcinoma types, As a result of loss of heterozygosity (LOH) studies in breast cancer, we delimited a genomic area within chromosome 16 that demonstrated the highest frequency of abnormalities. This led us to the identification and cloning of WWOX, a candidate tumor suppressor gene (TSG) that spans a fragile region of DNA located at 16q23.3-24.1 (FRA16D: the second most active common chromosomal fragile site in the human genome). This gene encodes a protein that contains two WW domains responsible of protein-protein interactions and a short-chain dehydrogenase (SDR) domain likely involved in sex steroid metabolism. Protein-protein interactions of WWOX with other peptides that act as apoptotic regulators as well as nuclear transcription factors have been described. We and other groups have studied the expression of WWOX in multiple tumor types in hormonally and nonhormonally regulated organs. In these studies, a significant correlation of loss of WWOX protein expression, with sex steroid hormone receptors expression and patient outcome, has been demonstrated. Reinsertion of the WWOX gene in WWOX-deficient tumorigenic cancer cell lines has shown a dramatic decrease of tumor growth in vivo, while inhibition of anchorage independent growth was observed in vitro. Further studies are necessary to elucidate the exact biological role of WWOX as a suppressor of tumor growth.