Stone attempted a return to the mainstream with a role in the film Catwoman (2004); however, the film was a critical and commercial flop. After years of litigation, Basic Instinct 2: Risk Addiction was released on March 31, 2006. A reason for a long delay in releasing the film was reportedly Stone's dispute with the filmmakers over the nudity in the movie; she wanted more, while they wanted less. A group sex scene was cut in order to achieve an R rating from the MPAA for the U.S. release; the controversial scene remained in the U.K. version of the London-based film. Stone told an interviewer, "We are in a time of odd repression and if a popcorn movie allows us to create a platform for discussion, wouldn't that be great?"

Despite an estimated budget of $70 million, it placed only 10th in gross on its debut weekend with a meager $3,200,000, and was subsequently declared a bomb. It ultimately ran in theaters for only 17 days and finished with a total domestic gross of under $6 million. Despite the failure of Basic Instinct 2, Stone has said that she would love to direct and act in a third Basic Instinct film.

She appeared in the drama Alpha Dog opposite Bruce Willis, playing Olivia Mazursky, the mother of a real-life murder victim. Stone wore a fatsuit for the role. In February 2007, Stone found her role as a clinically depressed woman in her latest film, When a Man Falls in the Forest, uplifting, as it challenged what she called "Prozac society." "It was a watershed experience," she said. "I think that we live in a... Prozac society where we're always told we're supposed to have this kind of equilibrium of emotion. We have all these assignments about how we're supposed to feel about something." In 2007, she appeared in a television commercial demonstrating the symptoms of a stroke.

• Streets of Blood (2009) (completed) .... Nina
  
• $5 a Day (2008) .... Dolores Jones
• The Year of Getting to Know Us (2008) .... Jane Rocket
• Democrazy (2007) .... Patricia Hill
  ... aka Demopazzia (Italy)
• When a Man Falls in the Forest (2007) .... Karen Fields
  ... aka When a Man Falls (USA: new title)
• If I Had Known I Was a Genius (2007) .... Gloria Fremont
  ... aka Genius: If Only I Had Known (USA: poster title)
• Bobby (2006) .... Miriam Ebbers
• "Huff" .... Dauri Rathburn (3 episodes, 2006)
       - Sweet Release (2006) TV episode .... Dauri Rathburn
       - Whipped Doggie (2006) TV episode .... Dauri Rathburn
       - Maps Don't Talk (2006) TV episode .... Dauri Rathburn
• Basic Instinct 2 (2006) .... Catherine Tramell
  ... aka Basic Instinct - Neues Spiel für Catherine Tramell (Germany)
  ... aka Instinto básico 2 - adicción al riesgo (Spain)
• Alpha Dog (2006) .... Olivia Mazursky
• Broken Flowers (2005) .... Laura
• "Will & Grace" .... Dr. Georgia Keller (1 episode, 2005)
       - The Blonde Leading the Blind (2005) TV episode .... Dr. Georgia Keller
• "Higglytown Heroes" .... Nicky - Blind Art Teacher (1 episode, 2005)
       - Twinkle's Masterpiece/The Egg-cellent Adventure (2005)
  TV episode (voice) .... Nicky - Blind Art Teacher
• "Kurtlar vadisi" .... Lisa (2 episodes, 2005)
  ... aka Valley of the Wolves (International: English title: literal title)
       - Episode #4.96 (2005) TV episode .... Lisa
       - Episode #4.97 (2005) TV episode .... Lisa
• Catwoman (2004) .... Laurel Hedare
• A Different Loyalty (2004) .... Sally Tyler / Cauffield
• "The Practice" .... Sheila Carlisle (3 episodes, 2003)
       - Blessed Are They (2003) TV episode .... Sheila Carlisle
       - Cause of Action (2003) TV episode .... Sheila Carlisle
       - The Chosen (2003) TV episode .... Sheila Carlisle
• Cold Creek Manor (2003) .... Leah Tilson
  ... aka Maison au fond de la baie, La (Canada: French title)
• "Harold and the Purple Crayon" .... Narrator (13 episodes, 2001-2002)