A slightly more polished album, As the Eternal Cowboy, was released in 2003 on the indie label Fat Wreck, followed by a compilation of that album's demos titled The Original Cowboy. After the release of a DVD (We're Never Going Home) and another 7", the band returned with its most mature effort to date, 2005's Searching for a Former Clarity. A subsequent headlining tour in support of the introspective, politically aggressive album saw Against Me! proudly hitting every U.S. state, and they signed with Sire Records in December 2005. Later they issued a rough version of Searching for a Former Clarity, titled Total Clarity. They were back on the road by spring 2006, this time opening for the Alkaline Trio, and spent the summer months playing the main stage at the Warped Tour. Though Against Me! were officially signed to Sire's roster, they released their last indie album in the form of Americans Abroad!!! Against Me!!! Live in London!!!, a concert album recorded while on tour in London with Murder by Death.
In July 2007, the band's major-label debut -- New Wave, a decidedly more rock-oriented record produced by Butch Vig -- hit shelves. New Wave was the first album by Against Me! with no acoustic tracks; it was also their first on a major label's tab. Reviews were generally favorable, and the band toured heavily in support of its release. By the summer of 2009, drummer Warren Oakes had officially left the group to pursue an alternate career as a restaurateur, eventually opening up a Tex-Mex eatery in Gainesville. Hot Water Music's George Rebelo joined in his place, and the revised lineup re-enlisted Butch Vig to produce the White Crosses album, which appeared in mid-2010. White Crosses debuted at 34 on the Billboard 200 and Against Me! were prepared to launch an international tour when they canceled a planned leg through Australia and New Zealand in September of 2010. Two months later, the band parted ways with Sire, and then prepared for some end-of-the-year shows with Jay Weinberg sitting in for Rebelo on drums, a move that was made permanent early in 2011. That spring, the demos collection Total Clarity appeared on Fat Wreck Chords, and as Against Me! started work on a new album, they launched their own record label called Total Treble Music; that year, Grace also opened an Elkton, Florida-based recording studio bearing the same name.
In a May 2012 interview with Rolling Stone, Laura Jane Grace went public with her gender dysphoria, announcing her plans to transition to living as a woman and abandon her birth name, Tom Gabel. Against Me! began working on a new album called Transgender Dysphoria Blues in 2012 and, a few months after the interview, the band played its first dates since Grace's news. Toward the end of the year, Weinberg left the troupe and, the following May, Against Me! announced bassist Andrew Seward had left the band. Laura Jane Grace continued working with guitarist James Bowman and the band released Transgender Dysphoria Blues to wide acclaim in January 2014. ~ Johnny Loftus, Rovi