Scissor Sisters were formed in 2001, and are named a sex position between 2 women. In 2000, Jake Shears (born Jason Sellards) met Babydaddy (born Scott Hoffman) while visiting a friend in Kentucky. They began to play music together, but it was generally poorly received. After moving to New York City, the duo met Ana Matronic (born Ana Lynch) at a Halloween cabaret. The group soon began playing gigs, and were joined by Del Marquis (born Derek Gruen), whom the band met whilst Shears was working as a stripper at a club called I.C. Guyz. Eventually the quartet signed to independent record label A Touch of Class, and recorded a single, "Electrobix", with the B-side a disco cover of Pink Floyd’s "Comfortably Numb". Paddy Boom (born Patrick Seacor) joined the band as a drummer, and in September 2003 Scissor Sisters were credited as the remixers of one of the versions of Blondie's hit single "Good Boys". Their cover of "Comfortably Numb" was picked up by underground DJs in electroclubs, began to gain recognition, and came to the attention of UK label Polydor, who signed them to a contract. First single for the label, "Laura", had a limited release in 2003, reaching number 54 on the UK Singles chart. "Comfortably Numb" was released as a single in it’s own right in 2004, featuring Paul Leschen on piano and keyboards, reaching number 10 in the UK. This was followed by "Take Your Mama" (number 17 in the UK), a re-release of "Laura" (number 12), "Mary" (number 14), and "Filthy/Gorgeous" (number 5). All these singles were from debut album ”Scissor Sisters”, which reached number 1 on the UK Album chart and became the best selling album of 2004. However, despite their UK success, ”Scissor Sisters” did not enjoy success in the US - "Take Your Mama" received popular radio airplay on US pop stations, and "Filthy/Gorgeous" enjoyed a following in gay clubs, and was featured in the soundtrack and ending cut-scene of Tony Hawk's “American Wasteland”, but the album was banned from the shelves of Wal-Mart due to its ‘coarse language’, and only made number 102 on the Billboard 200.

In late 2004, Shears and Babydaddy co-wrote and produced "I Believe in You" with Kylie Minogue, which featured on the “Ultimate Kylie” compilation. They also wrote the unreleased "(Everything) I Know", and "Ooh (The Blues)" (of which Kylie's version remains unreleased).

At the 2005 BRIT Awards, Scissor Sisters won “Best International Group”, “Best International Breakthrough” and “Best International Album”, the first time in the Awards history that an act had won all 3 International categories. Recording of second album, “Ta-Dah”, began May 2005, with Elton John collaborating with the band (as pianist and co-writer) the single "I Don't Feel Like Dancin'", which reached number 1 in the UK in September 2006, remaining there for 4 weeks, and topped the Australian ARIA Singles chart and the Euro Hot 100. “Ta-Dah” was released in September 2006, reaching number 1 in the UK Album chart in its first week of release (meaning that the Scissor Sisters had a single and album at the top of the UK charts simultaneously). It also enjoyed success in the US, making number 19 on the Billboard 200. "Land of a Thousand Words" was the second single, peaking at number 19 in the UK, but third single "She's My Man", released in February 2007, only peaked at number 29, and fourth single "Kiss You Off" (May 2007) failed to make the Top 40. In 2007, in the Doctor Who episode "Last of the Time Lords", the song "I Can't Decide" was used - it subsequently debuted at number 64 on the UK Singles chart despite not officially being released as a single.

In early 2008, online record label WHA!?, in association with Scissor Sisters fansite idontfeellikedancing.com released a free-to-download bootleg album entitled “Da-Tah”, featuring ‘mash ups’ of Scissor Sisters songs with songs by artists such as Beck, Peter Gabriel, Lauryn Hill and Nine Inch Nails. In October 2008, drummer Paddy Boom amicably parted from Scissor Sisters, his replacement being Randy 'Real' Schrager.