Transmembrane receptors, a subset of integral membrane proteins, are the receivers that transduce an extracellular chemical message into an intracellular response. Accordingly, these proteins are of particular interest in the scientific community and are probably best studied as part of a cellular system. Herein, we detail the engineering of a fluorescent and bioluminescent reporter cell line for a transmembrane receptor and how to employ it in a directed evolution screen that identifies peptide regulators of receptor activity.