The Janssen 4-anilidopiperidine class of opioid analgesics, i.e., fentanyl, sulfentanil, and alfentanil, have a number of advantages over morphine. They offer faster onset of action, greater potency, and in high doses the ability to produce a profound anesthetic state with efficient blockade of hormonal and stress responses to tracheal intubation and surgical incision. The shorter duration of action of alfentanil makes it amenable for short surgical and diagnostic procedures. Respiratory depression remains a side effect that warrants caution with the use of these drugs. This article reports the discovery of new 4-anilidopiperidines from which there are candidate drugs currently in development. Trefentanil, the first reported analogue of alfentanil with direct linkage of an aromatic ring to the 4-position of the piperidine, provides a shorter duration of anesthesia and opioid effects that is ideal for intraoperative use. Mirfentanil, the first 4-heteroanilido analogue of fentanyl to be chosen for drug development, has been shown to produce analgesic efficacy in the absence of significant respiratory depression. The pharmacological profiles of this Anaquest family of new 4-anilidopiperidines offer great promise for therapeutic advantages over current agents.