We report the latest structural information on PREP1 tumor suppressor, the specific “oncogene” and “tumor suppressive” signatures of MEIS1 and PREP1, the molecular rules regulating PREP1 and MEIS1 binding to DNA, and how these can change depending on the interaction with PBX1, cell‐type, neoplastic transformation, and intracellular concentration. As both PREP1 and MEIS1 interact with PBX1 they functionally compete with each other. PREP1, PBX1, and MEIS1 TALE‐class homeodomain transcription factors act in an interdependent and integrated (...) way in experimental tumorigenesis. We also pool together the plethora of data available in human cancer databanks and connect them with the available molecular information. The emerging picture suggests that a similarly basic approach might be used to better dissect and define other oncogenes and suppressors and better understand human cancer. (shrink)