The key to detecting and classifying drug effect at seven transmembrane (7TM) receptors is the pharmacological assay. Drug discovery had been rooted in testing of molecules on intact animal tissue until technology provided high-throughput binding assays for screening. While this allowed for the testing of large numbers of molecules, it also limited detection to molecules that interfere with the interaction of the receptor with a defined probe (i.e., radioligand). The ability to monitor functional changes in cells (recombinant or natural) provided a huge leap forward. Earlier functional assays were tied to specific signaling pathways (i.e., cyclic AMP and calcium) but now label-free assays in live cells provide the opportunity to detect more ligands and more fully characterize their efficacy. These ideas will be discussed in terms of harnessing the phenomenon of "functional selectivity" for therapeutic advantage.