Biologically active amines play major roles in the regulation of movement and are implicated in the pathophysiology of Parkinson’s and Huntington’s diseases, psychosis, and drug addiction. Fluorescent biosensors based on the biological macromolecule receptor are useful tool for investigating the function of biologically active amines. Our strategy of the stepwise molding using a ribonucleopeptide (RNP) framework provides fluorescent biosensors with a variety of binding and optical characteristics for small molecules. Here we report fluorescent RNP sensors for histamine with a variety of binding and signal-transducing characteristics. Combination of RNA subunits of histamine-binding RNP receptors obtained by in vitro selection and a Rev peptide modified with 7-methoxycoumarin-3-carboxylic acid afforded a fluorescent RNP sensor with distinct signaling characteristics in the changes of fluorescence emission intensity upon binding to histamine. The fluorescent histamine sensor showed distinct selectivity for histamine over structurally related histamine analogs, such as imidazole, ethylamine and L-histidine.