Starting at the latter part of the nineteenth century and through the early twentieth century, events are reviewed to provide a sense of the climate and setting in which early methadone research was conducted. The discovery of methadone by the Germans in the later stages of World War II is described. At that time, methadone was not recognized to be a narcotic analgesic. The first report of the properties of methadone published in the United States in 1947 is summarized, and its early use in the treatment of the opioid abstinence syndrome is noted. However, the utility of methadone as a maintenance drug was not recognized until 14 years later. Despite strong resistance from the U.S. Bureau of Narcotics, research progressed from the recognition of the unique properties of methadone to substantial clinical application. Finally, methadone is placed in a current context describing a second wave of acceptance based not solely on the reduction of crime but on the prevention of the spread of AIDS.