The BCL6 co-repressor (BCOR) is a transcription factor involved in the control of embryogenesis, mesenchymal stem cells function, hematopoiesis and lymphoid development. Recurrent somatic clonal mutations of the BCOR gene and its homologue BCORL1 have been detected in several hematological malignancies and aplastic anemia. They are scattered across the whole gene length and mostly represent frameshifts (deletions, insertions), nonsense and missence mutations. These disruptive events lead to the loss of full-length BCOR protein and to the lack or low expression of a truncated form of the protein, both consistent with the tumor suppressor role of BCOR. BCOR and BCORL1 mutations are similar to those causing two rare X-linked diseases: the oculo-facio-cardio-dental (OFCD) and the Shukla-Vernon syndromes, respectively. Here, we focus on the structure and function of normal BCOR and BCORL1 in normal hematopoietic and lymphoid tissues and review the frequency and clinical significance of the mutations of these genes in malignant and non-malignant hematological diseases. Moreover, we discuss the importance of mouse models to better understand the role of Bcor loss, alone and combined with alterations of other genes (e.g. Dnmt3a and Tet2), in promoting hematological malignancies and in providing a useful platform for the development of new targeted therapies.