Oct. 10, 2011— -- It's been 10 years since Rosie O'Donnell left her first enormously successful talk show -- "The Rosie O'Donnell Show" -- only now to be welcomed with open arms by the talk show queen herself, Oprah Winfrey.
"It's pretty exciting, I have to say it really is," O'Donnell told "Nightline" anchor Cynthia McFadden.
At 49, the Emmy-award winning comedian and actress is debuting her new talk show, "The Rosie Show," on the Oprah Winfrey Network (OWN) at 7 p.m. ET today. Her show is taped at the iconic Harpo Studios in Chicago, which was the home of "The Oprah Winfrey Show" for 25 years.
"I feel like was knighted by the queen...I will serve," O'Donnell said.
Her first guest will be actor Russell Brand, whom, O'Donnell jokes, has now replaced the man she used to idolize, Tom Cruise.
"Tom knows, I sent him a little text," she said. "I said, 'Tommy, I will always love ya. Move over, Russell Brand is in."
While filling Oprah's shoes may be daunting enough, Oprah herself said she isn't looking for a clone in O'Donnell.
"She is the only person in my 25-year reign as the number one talk show, the only person who came close to beating me was Rosie," Oprah said. "But it's not something I ever worried about. I am myself. Rosie is herself. I knew she had the goods. She had the goods."
Even much of Oprah's former staff has stayed on and begun adjusting to O'Donnell's way of running the show.
"I am not going to follow notes," O'Donnell said. "I read the books and I have a conversation. It's different than other talk shows. So it takes getting used to."
O'Donnell having been known for her sometimes controversial humor, bringing her back to television onto OWN was something Oprah handled personally. She flew out to meet with O'Donnell when she heard the comedian was considering a show with OWN.
"When I heard that Rosie actually might be interested in signing on with me and with OWN, I really couldn't believe it," Oprah said. "I was like, 'really? She would do that?' And you know, got on a plane to see her face to face to hear from her from her own lips that this is true because I didn't want agents speaking to lawyers and all of that stuff."
O'Donnell had a slightly different take on why Oprah wanted to come talk to her about launching her show.
"When I hugged her after I said I was all in, I said, 'so did you come here to see if I was insane?'" O'Donnell said. "She said, 'a little bit.' I said, 'I don't blame you.'...I passed the crazy check. I'm not sure how but I did."
For many fans, the last public sighting of O'Donnell was in 2007, when she and "View" co-host Elizabeth Hasselbeck had a painful falling out on camera.
"I learned that for me, if I can't be the boss of a show, I shouldn't be on the show," O'Donnell said.
Even though O'Donnell stands by her actions, she admitted to feeling uncomfortable with her behavior that day. She said she recently watched the video of that exchange on YouTube, and was "not OK with the level of anger."
She continued, "when I watched it back, I felt the betrayal and the sadness. I had worked very hard to sort of befriend Elizabeth."
Rosie O'Donnell on Suffering From Depression
O'Donnell says she does feel less angry these days, a tribute to discovering she needed to take hormones.
"I had zero levels of estrogen," she said, a discovery that was prompted by her friend Suzanne Somers, who urged her to get her levels checked.
"I started on bio-identical estrogen cream and I think it made a huge difference in my life," O'Donnell said.
While a visit to her new show reveals O'Donnell is upbeat, even zany in her opening monologue, she is also reflective and personal in an interview with Carrie Fisher about her weight loss and depression. Two topics close to O'Donnell's heart.
"That was a challenge my whole life," she said. "I was so grateful that I had gotten on medication after Columbine. I don't know how I would have gotten through 9/11...They say it's PTSD, I don't know, but it's a very big issue. In fact, when I took this job, I did say to Oprah, 'I'm pretty stable.' I'm doing really well, but I have to tell you, a world catastrophe, probably gonna need a week off."
With therapy and medication, the comedian says she is now feeling the best she has felt in a long time. And for O'Donnell, there is more to life than worrying about being a celebrity. Raising her four kids, Parker, 16, Chelsea, 14, Blake, 12, who were adopted, and Vivienne Rose, 9, who was conceived through artificial insemination, has been the most important thing to her.
"It is the best thing I ever did," O'Donnell said. "People sometimes say to me, 'oh, it was great of you to adopt,' and I say no it was greedy...I want to look into the eyes of that woman and that man who created those children and say, 'thank you, because you made my life worth living.'"
O'Donnell first married Kelli Carpenter, a former Nickelodeon marketing executive, in 2004. The couple divorced three years ago, and O'Donnell said she tried to date, but it wasn't easy.
By happenstance, she met her current girlfriend Michelle Rounds while standing in line at a Starbucks.
"I thought she was a 28-year-old heterosexual girl because that's what she looked like to me, and she's a 40-year-old gay woman," O'Donnell said. "My gaydar was way off."
One thing is for sure about the talk show host, she is not afraid of making a strong comeback. For O'Donnell, success means finding "a beautiful mix" of balance and happiness.