Gillis began experimenting with electronic music and sampling while a student at Chartiers Valley High School in the Pittsburgh, Pennsylvania suburb of Bridgeville. After a few collaborative efforts, he started the solo "Girl Talk" project while studying biomedical engineering at Case Western Reserve University in Cleveland, Ohio. In school, Gillis focused on tissue engineering.
Gillis states his musical inspirations to have been Squarepusher, Aphex Twin, Just Blaze, Nirvana and Kid606 among others. He has also stated interest in punk rock, as well as noise musician Merzbow. He stated that he was first introduced to the genre of Plunderphonics by John Oswald. Gillis has also stated that he was always into hip-hop and pop music. As he aged, he started to like older musicians such as The Beatles.
Gillis worked as an engineer, but he quit in May 2007 to focus solely on music.

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