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Born in Hartmannsdorf near Kirchberg in Saxony, Graupner received his first musical instruction from his uncle, an organist named Nicolaus Kuester. Graupner went to the University of Leipzig where he studied law (as did many composers of the time) and then completed his musical studies with Johann Kuhnau, the cantor of the Thomaskirche (St Thomas' Church).

In 1705 Graupner left Leipzig to play the harpsichord in the orchestra of the Hamburg Opera under the direction of Reinhard Keiser, alongside a young violinist named Handel. In addition to playing the harpsichord, Graupner composed six operas in Hamburg, some of them in collaboration with Keiser, a popular composer of operas in Germany.

In 1709 Graupner accepted a post at the court of Hesse-Darmstadt and in 1711 became the court orchestra’s Hofkapellmeister (court chapel master). Graupner spent the rest of his career at the court in Hesse-Darmstadt, where his primary responsibilities were to provide music for the court chapel. He wrote music for nearly half a century, from 1709 to 1754, when he became blind. He died six years later.

Graupner inadvertently played a key role in the history of music. Precarious finances in Darmstadt during the 1710s forced a reduction of musical life. The opera house was closed, and many court musicians' salaries were in arrears (including Graupner's). After many attempts to have his salary paid, and having several children and a wife to support, in 1723 Graupner applied for the Kantorship in Leipzig.

Telemann had been the first choice for this position, but withdrew after securing a salary increase in Hamburg. Graupner's "audition" Magnificat, set in the style of his teacher and mentor Kuhnau, secured him the position. However, Graupner's patron (the Landgrave Ernst Ludwig of Hesse-Darmstadt) would not release him from his contract. Graupner's past due salary was paid in full, his salary was increased; and he would be kept on staff even if his Kapelle was dismissed. With such favorable terms, Graupner remained in Darmstadt, thus clearing the way for Bach to become the cantor in Leipzig.

After hearing that Bach was the choice for Leipzig, on May 4, 1723 Graupner graciously wrote to the city council in Leipzig assuring them that Bach "is a musician just as strong on the organ as he is expert in church works and capelle pieces" and a man who "will honestly and properly perform the functions entrusted to him."

Graupner was hardworking and prolific. There are about 2,000 surviving works in his catalog, including 113 sinfonias, 85 ouvertures (suites), 44 concertos, 8 operas, 1,418 religious and 24 secular cantatas, 66 sonatas and 40 harpsichord partitas. Nearly all of Graupner's manuscripts are housed in the ULB (Technical University Library) in Darmstadt, Germany.

Graupner wrote for exotic combinations of instruments, including the oboe d'amore, flute d'amore, and viola d'amore. Over half of his sinfonias require brass and timpani, with about 25 sinfonias requiring 3 to 4 timpani, one (sinfonia in G Major GWV 611) 5 timpani, and another, sinfonia in F Major (GWV 566), was composed for 6 timpani.