The ESIPT process has the potential to allows for two wavelengths to be read out from a single molecule in a ratiometric fashion, but previous systems have primarily observed only subtle changes in the wavelength ratio due to nonspecific binding. The system we describe here exploits the environmental dependence of the ESIPT process where bulk water disrupts the efficiency of proton transfer in the excited state. The protein receptor was designed to selectively bind and desolvate an ESIPT fluorophore within a hydrophobic pocket. The result is a dramatic difference and inversion of the proportion of enol and keto emission. Finally, we note that benzoxazoles and benzothiazoles are privileged scaffolds in medicinal chemistry as they are found in numerous therapeutics displaying possess anticancer, antimicrobial, antiviral and anti-inflammatory properties, among others. Thus, we envision benzoxazoles may be utilized in diagnostic assays based on ESIPT fluorescence. We therefore anticipate this report to lay the groundwork towards the development of future ESIPT fluorescence based bioimaging technologies and monitoring of protein-protein interactions.