She has appeared in a number of films, including Galaxy Quest (1999), Josie and the Pussycats (2001), Bringing Down the House (2003), Dodgeball: A True Underdog Story (2004), Charlie and the Chocolate Factory (2005), Harold & Kumar Escape from Guantanamo Bay (2008), The Artist (2011), Gone Girl (2014), Captain Fantastic (2016), and Ma (2019).

[2] Pyle has also appeared in various television series, such as The Mentalist (2010), Cleaners (2013–2014), Jennifer Falls (2014), Another Period (2015–2018), Bordertown (2016), The Soul Man (2016), Mom (2017), Impulse (2018–2019), and Dirty John (2020).

Pyle has guest starred on many television shows, including Heroes, Mad About You, Boston Legal, Frasier, The Sarah Silverman Program, and 2 Broke Girls.

In 2008, Missi starred in the Broadway play Boeing-Boeing opposite Christine Baranski, Mark Rylance, Greg Germann, Paige Davis and Rebecca Gayheart.

Pyle was scheduled to ring the closing bell for the trading day at the New York Stock Exchange on September 29, 2008, to promote Boeing-Boeing, but backed out minutes before the close of trading so as not to associate herself with ending a calamitous day of financial turmoil which resulted in the Dow Jones Industrial Average losing 778 points, the largest point loss ever in a session in the wake of the financial crisis of 2007–2008.

The band started after Smith invited Pyle to join her in attending the Coachella Valley Music and Arts Festival.

The debut album was recorded in Joshua Tree, California at Rancho De La Luna and was produced by Chris Goss.