The MYB gene is expressed predominantly in immature progenitor cells of all hematopoietic lineages and is highly expressed in most leukemias and in some solid tumors. Translocations affecting MYB have been detected in T-cell acute lymphoblastic leukemia (T-ALL) and adenoid cystic carcinoma (ACC). Recent studies have identified a subgroup of T-ALL with reciprocal translocation t(6;7) (q23.3;q34) that juxtaposes MYB and TCRB (T-cell receptor beta locus) leading to the activation of MYB expression. Since the translocation breakpoints in 6q23 map to two clusters located 5 kb and more than 50 kb telomeric of MYB, no true MYB fusion gene is generated. It is assumed that the abnormal MYB expression could confer oncogenic properties and that MYB might represent a potential target for therapeutic intervention in T-ALL. In ACC a recurrent translocation t(6;9) (q22-23;p23-24) is found in about one third of karyotypically abnormal cases. The translocation results in the fusion of the two transcription factor genes MYB and NFIB (nuclear factor I/B) which leads to enhanced expression of the MYB-NFIB fusion protein. The detection of MYB rearrangements using FISH might represent a powerful adjunctive diagnostic tool useful in the differential diagnosis of ACC.