Three case studies will illustrate the concepts and the resultant clinical analgesic molecules. It is becoming increasingly common to hear a new analgesic drug molecule described as a “biased ligand,” being “peripherally restricted,” or as having been “engineered.” What do these terms mean? How are such drugs designed or discovered, and how do you even know that you have one when you have one? For that matter, how are any modern analgesic drugs designed or discovered these days? It’s definitely not your father’s preclinical drug discovery lab any more. Modern drug discovery labs utilize a variety of approaches such as compound libraries, combinatorial chemistry, fragment based lead discovery, high-throughput screening, in silico modeling, in vitro human receptor assays, CRISPR and AI (artificial intelligence).