Her fifth studio album Wildflower was released in September 2005. Although the album debuted at #2 on the Billboard charts, it received mixed reviews and was not as commercially successful as her previous albums. In December 2005, the album was nominated for a Best Pop Vocal Album Grammy, while Crow was nominated for a Best Female Pop Vocal Performance Grammy for the first single "Good Is Good". However, she ultimately lost in both categories to Kelly Clarkson. The album got a new boost in 2006 when the second single was announced as "Always on Your Side", re-recorded with British musician Sting and sent off to radio, where it was quickly embraced at Adult Top 40. The collaboration with Sting resulted in a Grammy-nomination for Best Pop Collaboration With Vocals. As of January 2008, Wildflower sold 949,000 units in the U.S.

In 2006, Crow contributed the opening track, "Real Gone", to the soundtrack for Disney/Pixar's animated film Cars. She also voices Elvis in the film. Crow was diagnosed with early-stage breast cancer in mid-February 2006. Her doctors have stated that "prognosis for a full recovery is excellent." Crow's first concert since her cancer diagnosis was on May 18 in Orlando, Florida where she played to over 10,000 information technology professionals at the SAP Sapphire Convention. Her first public appearance was on June 12, when she performed at the Murat Theater in Indianapolis, Indiana.

The singer also appeared on Larry King Live on CNN on August 23, 2006. In this show she talked about her comeback, her breakup with Lance Armstrong, her past job as Michael Jackson's backup singer, and her experience as a breast cancer survivor. In late 2006, Crow was nominated for a Golden Globe Award for the song "Try Not To Remember" (Best Original Song category) from the film Home of the Brave. Crow wrote a foreword for the book Crazy Sexy Cancer Tips, author Kris Carr's book that was based on her 2007 documentary film Crazy Sexy Cancer. Crow contributed her cover of the Beatles's "Here Comes the Sun" on the Bee Movie soundtrack in November 2007. She contributed background vocals to the Ryan Adams song "Two" from the album Easy Tiger.

• "Californication" (1 episode, 2008)
       - Blues from Laurel Canyon (2008) TV episode (performer: "Behind Blue Eyes")
• Karaoke Revolution Presents: American Idol Encore 2 (2008) (VG) (writer: "If It Makes You Happy")
• Fields of Fuel (2008) (writer: "Soak Up The Sun" (2002)) (performer: "Soak Up The Sun" (2002))
• Bee Movie (2007) (performer: "Here Comes the Sun")
• "Cold Case" (2 episodes, 2007)
       - Cargo (2007) TV episode (performer: "Good Is Good")
       - A Dollar, a Dream (2007) TV episode (performer: "Home")
• Grace Is Gone (2007) (writer: "Lullaby for Wyatt") (performer: "Lullaby for Wyatt")
• Home of the Brave (2006) (writer: "Try Not to Remember") (performer: "Try Not to Remember")
• 40th Annual Country Music Association Awards (2006) (TV) (performer: "Building Bridges", "What You Give Away")
  ... aka 40th Annual CMA Awards (USA: informal title)
• "Desire" (2006) TV series (unknown episodes)
• "The Sopranos" (1 episode, 2006)
       - Mayham (2006) TV episode (performer: "First Cut Is the Deepest")
• Cars (2006) (writer: "Real Gone") (performer: "Real Gone")
• "Shminiya, Ha-" (1 episode, 2006)
  ... aka The Eight (International: English title)
       - Little Red Riding Hood (2006) TV episode (performer: "Tommorow Never Dies") ("Tommorow Never Dies")
• "Charmed" (1 episode, 2005)
       - Hulkus Pocus (2005) TV episode ("Live It Up")
• "Rescue Me" (1 episode, 2005)
  ... aka Rescue Me: FDNY (USA: complete title)
       - Believe (2005) TV episode (performer: "I Shall Believe")
• Must Love Dogs (2005) (performer: "The First Cut Is The Deepest")
• Kiss Kiss Bang Bang (2005) (performer: "BLUE CHRISTMAS")
• "The Oprah Winfrey Show" (1 episode, 2005)
  ... aka Oprah (USA: short title)
       - Episode dated 11 February 2005 (2005) TV episode (performer: "I Know Why")
• "The Wire" (1 episode, 2004)
       - Back Burners (2004) TV episode (performer: "Strong Enough") ("Strong Enough")