The chemistry that underlies the development of local and regional anesthesia is explored. Starting from the first medicinal use of cocaine as a topical anesthetic in 1884, the gradual advancement of knowledge and practice until today is presented. In so far as possible, the original synthesis of each agent is included. Emphasis is placed upon the importance of acidity constants and lipophilic versus hydrophilic character in interpreting what affect a particular compound has upon biological processes. Two examples of current hospital practices are included.

In this article we summarize the first one hundred and ten years of general anesthesia from 1846 to 1956. Although the medical profession was slow to use ether or chloroform induced anesthesia, by the end of the 19th century significant numbers of surgeons were relying upon these volatile liquids to provide unconsciousness, analgesia, muscle relaxation, and amnesia. Events leading up to the adoption of a "balanced" approach, where a sequence of individual compounds is used rather than a single agent, are described. The process began in 1934 with the first use of thiopental as an intravenous induction anesthetic and was advanced with the use of the muscle relaxant curare in surgery in 1942. Synthesis of a new inhalational anesthetic, halothane, in the 1950s provided the third and final element. Original syntheses of compounds are included, as are correlations of activities with structures.

Contemporary anesthetists have access to a broad spectrum of medicinals for use during presurgery, intraoperational events, and postoperative recovery. With the basic elements of balanced general anesthesia in place by the 1950s, the focus turned to developing safer and more effective agents and to improving procedures. During the last half-century a new generation of intravenous induction anesthetics, inhalational anesthetics, and muscle relaxants has emerged. Details of their syntheses are included along with structure–activity correlations.