The PRDM family of proteins share a unique structure, with an N-terminal PR domain, which has a potential methyltransferase activity, followed by a distinct number of zinc fingers at the C-terminus, potentially mediating protein–protein, protein–RNA or protein–DNA interactions. Interestingly, despite no comprehensive functional data, all family members have been associated with deletions, mutations, epigenetic silencing or overexpression, in multiple cancer types. The intriguing observation is that different isoforms exist for almost all PRDM family members. These isoforms are not only differentially regulated, but play opposite roles in cancer, in what has been termed ‘Yin and Yang’ regulation, typical of this class of epigenetic regulators. Collectively, these findings set the stage for future intervention, by targeting directly their intrinsic catalytic activities, or indirectly, pathways that differentially regulate tumor suppressor/oncogenic isoform-expression.