Deletions and translocations at 5q13 point out a locus involved in the development of acute myeloblastic leukemia (AML) and myelodysplastic syndromes (MDS) as well as other neoplasms. The chromosomal rearrangements of 5q13 are well documented, but have not been a primary focus of research. In this report, we provide evidence for a novel critical locus at 5q13.3, encoding gene(s) which may be disrupted by chromosomal translocations or deletions. Rare cases of myeloid neoplasms with t(5q13) as the sole chromosomal anomaly argue for a gene which gives rise to fusion proteins. Our preliminary studies have localized one of the critical genes to a <3 Mb. interval between the polymorphic markers AFMB347yf9 and GATAP18104 at the band 5q13.3. Other results also suggest that the 5q 13.3 locus may span a fragile site which undergoes unbalanced translocations and interstitial deletions accompanied by loss of significant segments of chromosome 5. Molecular reagents generated by the human genome mapping and sequencing initiative will allow us to characterize the critical genes at 5q13.3 and facilitate genotypic analysis of AML and MDS.