The CREBBP protein regulates transcription by means of histone acetyltransferase activity and by binding to several proteins with key cell cycle functions, such as p53 and NFκB. Rearrangements of the CREBBP gene have been observed in several hematologic malignancies. Three different fusion partners have been described so far. KMT2A (a.k.a MLL) is fused to CREBBP in therapy-related acute myeloid (AML) or lymphoid leukemia (ALL) and myelodysplastic syndrome (MDS) with t(11;16)(q23.3;p13.3). The translocation t(10;16)(q22.2;p13.3) was reported in some AML cases and fuses KAT6B (a.k.a. MORF) to CREBBP. CREBBP is also rearranged with KAT6A (a.k.a. MOZ) in de novo and therapy-related AML with t(8;16)(p11.2;p13.3) after treatment with topoisomerase II inhibitors. This rearrangement is associated with an infrequent but well-defined type of AML that has characteristic morphocytochemical features. The prognosis is usually extremely poor, with a median survival of two months. The KAT6A/CREBBP AML tends to develop within two years of adjuvant chemotherapy, especially in former breast cancer patients. Thus, FISH analysis for the detection of CREBBP translocation may serve as a diagnostic tool to identify cases with hematologic malignancies with an aggressive presentation.