Cells possess numerous receptors that modulate signaling pathways. While hundreds of thousands of receptor sequences are available in databases, the signals that receptors recognize remain largely unknown. Here, we used a structure/sequence approach to identify thousands of microbial proteins with the predicted capability to detect biogenic amines. We selected several targets for experimental validation and demonstrated that all of them bind various amines. Amines are key nutrients and major neurotransmitters. Identification of amine sensors in bacteria inhabiting the human gut as well as in plant- and human pathogens opens research directions for those studying these important microbes. By revealing that amine-sensing receptors originated from amino acid–sensing receptors, we show how receptors can change their specificity during evolution.