Thioredoxin binding protein (TXNIP) has multiple functions and plays an important role in redox homeostasis. TXNIP increases the production of reactive oxygen species (ROS), and oxidative stress, resulting in cellular apoptosis. It has been identified as a tumor suppressor gene (TSG) in various solid tumors and hematological malignancies. In the present review, we will first provide an overview of TXNIP protein and function, followed by a summary of the major studies that have demonstrated the frequent repression of TXNIP in cancers. Functional characterization of TXNIP knockout mouse model is summarized. We will then discuss the use of small molecular inhibitors to reactivate TXNIP expression as a novel anticancer strategy.