In the late 2000s, Shields guest-starred on shows like FX's Nip/Tuck and CBS' Two and a Half Men. In 2005, Shields appeared in a season-two episode of HBO's Entourage, entitled "Blue Balls Lagoon." In 2007, she made a guest appearance on Disney's Hannah Montana, playing Susan Stewart, Miley and Jackson's mother, who died in 2004. In 2008, she returned in the primetime drama Lipstick Jungle. The series ended a year later.
In May 2005, Tom Cruise, an actor and Scientologist whose beliefs frown upon psychiatry, condemned Brooke, both personally and professionally, for both using and speaking in favor of the antidepressant drug Paxil. As Cruise said, "Here is a woman and I care about Brooke Shields, because I think she is an incredibly talented woman, you look at [and think], where has her career gone?" Shields responded that Cruise's statements about anti-depressants were "irresponsible" and "dangerous." She said that he should "stick to fighting aliens" (a reference to Cruise's starring role in War of the Worlds as well as some of the more esoteric aspects of Scientology doctrine and teachings), "and let mothers decide the best way to treat postpartum depression." The actress responded to a further attack by Cruise in an essay "War of Words" published in The New York Times on July 1, 2005, in which she made an individual case for the medication and said, "In a strange way, it was comforting to me when my obstetrician told me that my feelings of extreme despair and my suicidal thoughts were directly tied to a biochemical shift in my body. Once we admit that postpartum is a serious medical condition, then the treatment becomes more available and socially acceptable. With a doctor's care, I have since tapered off the medication but, without it, I wouldn't have become the loving parent I am today." On August 31, 2006, according to USAToday.com, Cruise privately apologized to Shields for the incident. Shields accepted Cruise's apology, which she said was "heartfelt." Three months later in November 2006, she and her husband attended the wedding of Cruise and Katie Holmes.