Following a series of appointments as conductor at Darmstadt, Barmen-Eberfeld, Düsseldorf, and Mannheim, he became general music director of the Berlin State Opera in 1923. In addition to the mainstream repertory, Kleiber introduced unfamiliar works such as Schoenberg's Pierrot Lunaire, Janacek's Jenufa, Bittner's Das Rosengärtlein, and, after an astounding 132 rehearsals, gave the first U.S. performance of Berg's Wozzeck in 1924. His U.S. debut as an orchestral conductor was with the New York Philharmonic Orchestra in 1930. As conductor of the Berlin Philharmonic Orchestra and a friend of Alban Berg, Kleiber was planning a Berlin performance of the five symphonic interludes from Berg's opera Lulu, but, incensed by the Nazi regime's hostility to atonal music and growing political interference in his choice of programs, he resigned his Berlin post in 1934, left Germany, and appeared as guest conductor in London, Prague, Brussels, Buenos Aires, Amsterdam, and Salzburg. In 1939, Kleiber took up residence in Buenos Aires and became an Argentine citizen. He conducted opera at the Teatro Colón, trained the Buenos Aires Symphony Orchestra and toured extensively in South America with various orchestras. From 1943 he was with the Havana Philharmonic Orchestra, leaving for Europe in 1948.
In postwar Europe, Kleiber was ready to return to his roots. In 1951, he accepted the position of conductor at the Berlin State Opera, then located in the Communist sector of East Berlin, and from 1950 to 1953 conducted at London's Covent Garden opera house. Once again, however, he became dissatisfied with the atmosphere of repression and resigned his Berlin post in 1955. Before his relatively early death, he appeared as guest conductor of orchestras in London, Vienna, Cologne, Stuttgart, and other European centers.
Despite his early enthusiasm for twentieth century music, Kleiber is best remembered for minutely rehearsed and finely balanced interpretations of Beethoven, Mahler, and Bruckner. Even when in Berlin, where much of the Classical and Romantic repertory was familiar to the performers, he usually called five rehearsals before a concert. A perfectionist by nature, he insisted on complete faithfulness to the score. In his words, "[t]here are only two enemies of good performance: one is routine and the other improvisation." Kleiber's recorded performances are confined mainly to the last 10 years of his life when under contract to Decca. His Beethoven Fifth Symphony has been called the finest recorded interpretation of this much-recorded work. His son Carlos, himself a distinguished conductor, made an equally celebrated recording of the same work in 1975. Nevertheless, Erich Kleiber was never satisfied with his own interpretation of Beethoven's Third ("Eroica") Symphony, and would not allow Decca to release it. After his death, a performance by the Vienna Philharmonic Orchestra became available on CD, as did the Rosenkavalier he recorded in 1954.