A research chemist at the J.R. Geigy Company, Basel (1925–65), Müller began his career with investigations of dyes and tanning agents. In 1935 he began his search for an “ideal” insecticide, one that would show rapid, potent toxicity for the greatest number of insect species but would cause little or no damage to plants and warm-blooded animals. He also required that it have a high degree of chemical stability, so that its effect would persist for long periods of time and its manufacture would be economical. Four years later Müller tested a substance known as dichlorodiphenyltrichloroethane (DDT) and found that it satisfied these requirements. The German chemist Othmar Zeidler had first synthesized the compound in 1874 but had failed to realize its value as an insecticide.

In 1939 DDT was tested successfully against the Colorado potato beetle by the Swiss government and by the U.S. Department of Agriculture in 1943. In January 1944 DDT was used to quash an outbreak of typhus carried by lice in Naples, the first time a winter typhus epidemic had been stopped.

Although Müller had required his ideal insecticide to be relatively nontoxic to warm-blooded animals, the widespread use and persistence of DDT (in 1968 it was estimated that 1,000,000,000 pounds 【453,000,000 kg】 of the substance remained in the environment) made it a hazard to animal life, and it showed signs of disrupting ecological food chains. By 1970 DDT was rapidly being supplanted by more quickly degraded, less toxic agents; its use was banned in a number of countries.