E VER SINCE the introduction of cocaine as a local anesthetic into medical practice by Keller, 1 it has been known that these agents are a double-edged sword providing immense benefits as well as a potential for toxicity. While describing the effects of cocaine, and also acting as guinea pigs for their research, Halsted and Hall in New York became cocaine addicts. 2 The quest for safer local anesthetics began toward the end of the 19th century, soon after the toxic effects of cocaine became known. Around the dawn of the 20th century, three cocaine substitutes, tropocaine, stovaine, and novocaine, were tried. In 1943, Lofgren 1 synthesized the amide-linked local anesthetic lidocaine; this started the practice of regional anesthesia with which we are familiar today. Lidocaine had a short duration of action; thus, the longer-acting bupivacaine and etidocaine were introduced in clinical practice (in the 1970s in the United States). The latter two had their own problems, and the search for a safe and efficacious local anesthetic continues with the introduction of ropivacaine. This review will focus on the factors influencing local anesthetic toxicity: the manifestations, underlying mechanisms, and prevention and treatment of central nervous system (CNS) and cardiovascular system toxicity. The incidence of toxic events is not well documented. However, it is reasonable to state that in performing a major nerve block (exclusive of spinal anesthesia), the patient is more likely to experience a CNS or cardiovascular reaction than to suffer permanent nerve damage, but is far less likely to experience one of these events than to have a failed anesthetic. We now know that these anesthetics exert their