After years of development, total internal reflection imaging ellipsometry (TIRIE) biosensor has advanced from a concept to a practical analysis tool for biomolecule interactions. Compared to the traditional biosensor with imaging ellipsometry (BIE) which works under the external reflection condition, not only does TIRIE biosensor perform the label-free, high throughput detection, but also remains competitive detection sensitivity. The review summarizes the principle, the equipment setup, and the current applications of TIRIE biosensor. © 2019 Author(s).