The luminescence sensing of histidine and histidine-rich proteins plays a pivotal role in biochemistry and molecular biology, in particular when both temporal and spatial resolution are required. An abnormal level of histidine-rich proteins is an indicator for many diseases, such as advanced liver cirrhosis, [1a,b] AIDS, [1c] renal disease, [1c] asthma, [1c] pulmonary disorders, [1d] thrombotic disorders, [1e, f] and malaria.[1g]Some analyses of histidine and histidine-rich proteins have been developed in conjunction with immunoassay [2a-d] and colorimetric detection methods.[2e] The most commonly used method for the detection of histidine and histidine-rich proteins in biological samples is chromatography, which is usually performed through the combination of an effective separation technique, such as thin-layer chromatography, gas chromatography, or HPLC, followed by UV/Vis or fluorescence spectroscopy.[2f-h] The use of high-performance capillary electrophoresis with a derivation reagent has also been reported.[2i] However, the aforementioned methods are generally tedious, laborious, and, most importantly, expensive for routine detection in a biochemistry laboratory.Although numerous studies have dealt with the detection of histidine or histidine-rich proteins, studies on the use of luminescent probes for this purpose remain sparse.[3] Notable examples include research by Fabbrizzi and co-workers, who developed competitive noncovalent fluorescence turn-on probes for histidine in the form of dizinc(II) or dicopper(II) macrocyclic complexes, which recognize histidine through the formation of an imidazolate bridge between the two dizinc(II) or dicopper(II) centers; [3a] however, the resulting noncovalent ensemble may be less stable than a covalently linking sensory system, and the complexity of the synthetic process makes it difficult to implement in a convenient manner.Photoluminescent iridium(III) complexes have emerged as a topical area of interest in inorganic photochemistry [4] and phosphorescent materials for optoelectronic [5] and luminescence signaling applications.[6] Significant changes in the photophysical behavior and emission properties of iridium-(III) complexes may be induced by the presence of biomolecules. Luminescent transition-metal complexes for protein staining, such as the luminescent ruthenium complex known as SYPRO Ruby dye, have been reported previously. [7] However, despite its high sensitivity and its broad dynamic range, the use of SYPRO Ruby dye is limited, as it is sold only as a formulated solution; therefore, it is not possible to optimize the dye for a particular electrophoresis protocol and protein. + , and the iridium complex is readily soluble and stable in aqueous staining solutions. In this study, [Ir(ppy) 3 ] (2) was also prepared for comparative studies, as its binding with proteins was expected to be largely hydrophobic in nature. Herein, we describe the luminescent switch-on probe [Ir(ppy) 2 (solv) 2 ] + (1) for histidine/histidinerich proteins and demonstrate...