Biomolecular engineering has many applications in the identification of potentially therapeutic compounds. An important class of these compounds is those that bind and modulate the activity of the human nuclear hormone receptors (NHRs). NHRs are typically made up of clearly defined domains with known function, including one that mediates ligand recognition and NHR activation. Engineered systems that include these ligand-binding domains (LBDs) can be used to identify potential therapeutic ligands that target a given NHR. These methods must couple the binding event to a readily detectable signal, ideally in a high-throughput format. Recent efforts have delivered a variety of new techniques, including those that involve fusions of LBDs to easily assayed reporter proteins. In some cases these systems allow hormone-dependent selectable phenotypes to be generated in non-native hosts, providing potential tools for both isolation and evolution of new therapeutics in vivo. Here we provide an overview and a comparison of many of the available tools in this area, with an emphasis on a novel allosteric hormone-regulated sensor protein that provides ligand-dependent phenotypes in the relatively simple background of Escherichia coli bacterial cells.