O'Donnell, the third of five children, was born and raised in Commack, Long Island, New York. She is the daughter of homemaker Roseann Teresa (nee Murtha) and Edward Joseph O'Donnell, an electrical engineer who worked in the defense industry. O'Donnell's father had immigrated from County Donegal, Ireland, during his childhood, and her mother was Irish American; O'Donnell was raised Roman Catholic. Her older brother is Daniel J. O'Donnell, now a member of the New York State Assembly.

In March 2007, O'Donnell started a video blog, Jahero, on her website Rosie.com answering fans questions, giving behind the scenes information and serving as a video diary. Originally featuring only O'Donnell and her hair and make-up artist Helene Macaulay they were soon joined by her writer from The Rosie O'Donnell Show, Janette Barber. Called Jahero, a name composed of the first two letters of each of their first names, they occasionally had short cameo appearances by View co-hosts Joy Behar, Elisabeth Hasselbeck, and Barbara Walters. Jenny McCarthy appeared once briefly, as has Hasselbeck's mother-in-law and O'Donnell's mother-in-law, her (now) ex-wife Kelli's mother. Kathy Griffin also appeared, where she read some of the questions. It became so popular that O'Donnell and her creative team considered an "on the road" version of the video blog utilizing fan-submitted suggestions. O'Donnell was the front runner for the "best celebrity blogger" category in the 2007 Blogger's Choice Awards which she won. O'Donnell expressed interest in replacing long-time host Bob Barker when he retired from CBS's game show The Price Is Right. Barker was a frequent guest on her talk show and told reporters that she "would make a fine host." Although it was reported he had "endorsed" her as a "possible successor", Barker said that he had no role in choosing his replacement. In June 2007, she announced on her blog it was not going to happen and noted she was reluctant to uproot her family to move to California. In 2008, O'Donnell starred in and executive produced America, a Lifetime channel original movie in which she plays the therapist of the title character, a 16-year-old boy aging out of the foster care system. The film is based on the E.R. Frank book of the same name. In October 2009, she appeared in the original cast of Love, Loss, and What I Wore. In November 2009 ,"Rosie Radio", a daily two-hour show with O'Donnell discussing news and events on Sirius XM Radio, premiered. O'Donnell said she was approached by the company after she appeared on Howard Stern's Sirius XM show. The radio show ended in June 2011.

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did she replace bob barker?