Agents to treat anxiety have gained in acceptance and importance in the fast pace of life in the second half of this century. The discovery and refinement of the benzodiazepines represented a quantum leap in therapy from early compounds which were essentially sedatives. With the advent of molecular biology, an understanding of the basic mechanism by which the benzodiazepines exert their effects was revealed through the discovery and isolation of the GABAA receptor and its benzodiazepine binding site. This, in turn, has enabled benzodiazepines to be classified into a broad spectrum of pharmacological types ranging from agonist to inverse agonist, thus allowing fine tuning with respect to side-effects. Consequently, newer, more promising agents have emerged which bind at the GABAA BZD site and have reduced side-effects. An example of this is RWJ-51204 (92), a member of a novel structural type which is superior to several marketed benzodiazepines in animals in terms of efficacy and side-effects. The cost-conscious environment of managed health care presents continuing challenges to the discovery and development of safe, highly efficacious, and cost-effective anxiolytic agents.