The proto-oncogenic properties of the POK family of transcriptional repressors BCL6, PLZF, and LRF have been well established. These proteins utilize their amino-terminal POZ domains for multimerization and the recruitment of co-repressors. Because LRF represses the production of the tumor suppressor p19^Arf (ARF), it is regarded as an attractive therapeutic target for the treatment of many types of cancer. The crystal structure of the LRF POZ domain reveals a high degree of structural conservation with the corresponding domains of BCL6 and PLZF. However, striking differences between the electrostatic properties of the BCL6 and LRF POZ domains suggest that if, like BCL6, LRF interacts with the co-repressor SMRT, it almost certainly uses a different mechanism to do so. These differences may also explain why LRF interacts with BCL6 but not with PLZF. Finally, the conservation of crystal packing contacts suggests the probable location of the interface that mediates LRF/BCL6 complex formation.