One of the most interesting and disease related regions of the human genome is contained in an area of approximately 20 million base pairs of DNA encompassing bands 3pl4.2 to 3p2l.1 (fig. 1). Within this region is the most common constitutive fragile site in the genome, the location of the hereditary renal carcinoma 3;8 translocation, a putative tumor suppressor gene, the site of the developmental Greig Polysyndactyly craniofacial anomalies syndrome 3;7 translocation, as well as a 3;6 translocation occurring in a family with hereditary hematologic malignancies. The density of these chromosomal landmarks associated with important biological disorders makes this region especially amenable to a reverse genetic approach for the purpose of isolating and characterizing those genes at or near the sites of the chromosomal rearrangements. Our current studies, in progress for little more than two years, have resulted in the isolation and mapping of approximately 370 probes from human chromosome 3, a partial pulsed-field map of the 3p14-21.1 region, and identification and characterization of the Greig polysyndactyly 3;7 translocation. We have also obtained confirmatory evidence that the mouse mutant extra-toes (Xt) is the homologue of the human Greig Syndrome, thereby providing a model for the study of this disorder. This background forms the basis for our proposed studies to molecularly clone the Greig polysyndactyly t3;7 and hereditary renal cell carcinoma t3;8 translocation breakpoints, and to identify and characterize the genes which are altered as a result of these rearrangements.