Zinc finger protein ZBTB20 is a novel member of the ZBTB zinc finger protein family and shares closest homology with BCL-6 and PLZF. Recent studies on genetically modified mice and patient cohort have revealed that ZBTB20 plays indispensable roles in multiple organs and systems, including the nervous system, liver, pancreatic islets, and immune system. ZBTB20 is an essential regulatory factor in a variety of physiological processes, such as ontogenesis, pain sensation, learning and memory, as well as glucose and lipid metabolism. Meanwhile, recent researches have also showed a close relationship between the abnormality or dysfunction of ZBTB20 and pathophysiological procedures of diseases, such as maldevelopment, mental retardation, tumors and metabolic disorders. As a key repressor governing AFP gene transcription, ZBTB20 exerts a great influence on the gene inactivation of liver AFP after birth and is closely related to the prognosis of hepatocellular carcinogenesis. In humans, the deletion of ZBTB20 is detected in diverse tumors and its point mutation leads to Primrose syndrome. This review summarizes the current knowledge concerning the biological functions of ZBTB20.