The FRA3B at 3p14.2 is the most common of the constitutive aphidicolin-inducible fragile sites. Using independent approaches, four groups of investigators have cloned and characterized this fragile site. The results of these studies have revealed that the FRA3B differs from other heretofore cloned rare fragile sites. First, instability as manifested by chromosome breakage occurs over a large region of DNA, encompassing at least 500 kb. Second, sequence analysis has not revealed trinucleotide repeat motifs, characteristic of the rare fragile sites. In addition to containing the FRA3B, band 3p14 is also likely to contain a tumor suppressor gene, as evidenced by the presence of deletions, rearrangements, and allele loss in a variety of human tumors, including lung, renal, nasopharyngeal, cervical, and breast carcinomas. The recently cloned FHIT gene in 3p14.2 is a promising candidate tumor suppressor gene, since aberrant FHIT transcripts have been found in a significant proportion of cancer-derived cell lines and primary tumors of the digestive and respiratory tracts. Nonetheless, several lines of evidence garnered over the past year have called into question the role of FHIT as a classical tumor suppressor gene, and raised the question of whether its apparent involvement simply reflects its location within an unstable region of the genome. In the following study, we have summarized the evidence in support of FHIT as a tumor suppressor gene as well as evidence against such a role, and the experimental evidence needed to demonstrate that FHIT functions as a tumor suppressor gene in the pathogenesis of human tumors. The paradigm of FHIT emphasizes that confirming the role of a candidate tumor suppressor gene may prove difficult, particularly for those genes that are located in genetically unstable regions.