The resonant mirror (RM) biosensor is a leaky waveguide-based instrument that uses the evanescent field to probe changes in the refractive index at the sensing surface.The RM can therefore be used to monitor in real-time and label-free the interaction between an analyte in solution and its biospecific partner immobilized on the waveguide surface.The RM has been used in studying the interaction of a variety of moieties including proteins, carbohydrates, cells, nucleic acids and receptors, leading to applications in areas such as clinical diagnostics, homeland security, and pharmaceutical and biomolecular interactions. This chapter will review the principle of this biosensor, and the recent advances in instrumentation, different immobilization chemistries, and kinetic studies, as well as some applications.