It was her breakout role when it hit screens in 2005 and to this day Grey's Anatomy remains Katherine Heigl's most high-profile gig.
The hit medical drama, in which she played medical intern Dr Isobel Stevens, made an immediate star of Heigl.
But it also was the catalyst for her rapid downfall.
Before landing the role of "Izzie", Heigl was yet to make a huge impact despite appearing in several movies and TV shows since her debut film, That Night, in 1992.
She was a regular in the '90s teen hit Roswell, where she gained notoriety for being attractive.
Heigl, now 40, then nabbed decent roles in the TV series Wuthering Heights, sport comedy film The Ringer and as Romy in the 2005 television film Romy and Michele: In the Beginning.
And then Grey's Anatomy happened. The show, which also starred Patrick Dempsey, is one of the highest rating broadcast TV shows ever and catapulted its cast to extreme success; none more so than Heigl.
In 2007, two years after she started on Grey's, Heigl appeared as a lead role in the successful movie Knocked Up, alongside Seth Rogen, for which she earned a decent $US300,000.
Later that year, Heigl became the only Grey's series regular to ever win an Emmy for acting on the show, winning the Best Supporting Actress — Drama award in 2007.
Off the back of her Emmy win, and the success of Knocked Up, Heigl was in prime position to command big salaries.
Only a year after taking home a $300,000 pay cheque in Knocked Up, she made an eye-watering $US6 million for the romantic comedy, 27 Dresses.
That's a 1900 per cent pay rise in a matter of months. Yes. 1900 per cent. 20 times the amount.
But it wasn't just her pay packet and her star that was rising. She also became a huge celebrity, as a regular on Hollywood's sexiest lists and magazine covers.
In 2008, Heigl was announced the Most Desirable Woman, according to AskMen.com.
Women wanted to be her and men wanted to date her.
She was expected to win the Emmy yet again for her work on Grey's Anatomy.
And then she did something that to this day she has never fully recovered from.
In a statement, Heigl announced she had pulled out of Emmys contention because she didn't think her role in season 4 was "given the material" to warrant a win.
"I did not feel that I was given the material this season to warrant an Emmy nomination and in an effort to maintain the integrity of the academy organisation, I withdrew my name from contention," she confessed.
"In addition, I did not want to potentially take away an opportunity from an actress who was given such materials."
It caused absolute upheaval not only among fans but Heigl's co-stars and crew, who deemed it an insult toward their veteran showrunner and series creator, Shonda Rhimes.
Rhimes noted at the time that Heigl's character was downplayed during the season because Heigl herself had asked for a lighter work schedule
There were reports of tension on set, with rumours swirling Heigl wanted to leave the series in 2008 and 2009 and was behaving like a "diva".
However, despite reports her character would be killed off, she signed on for another season.
Despite her reputation suffering a setback, Heigl managed to pick up three big budget movie roles.
She starred with Gerard Butler in romantic comedy The Ugly Truth (2009). The film was a success, made on a budget of $38 million and earning $205 million at the worldwide box office.
In 2010, Heigl starred in the Lionsgate comedy-thriller Killers, with Ashton Kutcher, and next featured in and produced the big-screen drama Life As We Know It, alongside Josh Duhamel, where she received a handsome $12 million for both movies.
But while she was having no issue securing roles and making big money, Heigl was the subject of incessant negative media reports over her behaviour on set of Grey's.
On March 11, 2010, Heigl reportedly did not show up for work on the show, and Rhimes reached an agreement to immediately release Heigl from her contract.
It was abrupt, as viewers had already watched her final episode without even realising it.
Two years later, Rhimes told Oprah Winfrey Heigl's Emmys statement "stung".
"On some level it stung and on some level I was not surprised," she said.
"When people show you who they are, believe them. I carry that with me a lot. It has served me well."
But Rhimes got a little more savage about Heigl as time went on.
In 2014, in an interview with The Hollywood Reporter, she referenced the movie star when talking about her new show, Scandal, saying "there are no Heigls" on set.
"I don't put up with bullshit or nasty people," she said of her "no assholes policy".
To say Heigl's career has never recovered since her departure from Grey's is an understatement.
In 2011, Heigl appeared in the ensemble romantic comedy New Year's Eve, directed by Garry Marshall. It was a commercial success, but it received harsh reviews.
Heigl next had the lead role in One for the Money (2012), which was a financial bomb, grossing just $36 million worldwide against its production budget of $40 million.
To top it off, Heigl received a Golden Raspberry Award nomination for Worst Actress.
Two years after she left Grey's, Heigl said she asked the producers if she could return to finish Izzie's storyline.
"I really, really, really want to see where (Izzie) is," she said.
"I just want to know what happened to her and where she went and what she's doing now. "My idea is that she actually, like, figures it out, and finds some success and does really well in a different hospital. She was always floundering, you know, and so she was always one step behind the eight ball and I want to see that girl take some power back."
Heigl then made the startling admission that she regretted leaving the show.
"Oh yeah, sometimes, yeah. You miss it. I miss my friends. It was a great work environment … and it becomes a family. I spent six years together with these people every day … you grow up together, in a way," she added.
"I always felt that if they wanted me to come back and sort of wrap up that storyline … I want them to know that I'm down with it if they want me to, but I completely understand if it doesn't necessarily work … They've got a lot of storylines going on there."
In 2013, Heigl appeared alongside Robert De Niro, Diane Keaton and Susan Sarandon in The Big Wedding, a comedy about an estranged family reuniting for a ceremony.
It received a nightmare critical and commercial reception, making $7.5 million in its opening weekend, and Heigl was nominated for Worst Supporting Actress at the 34th Golden Raspberry Awards.
The following year, Heigl starred in the romantic drama Jackie & Ryan, opposite Ben Barnes.
In an ultimate snub for any actor, the film was released in a limited release and through video on demand.
Her career in a massive slump, Heigl opened up to Marie Claire and said the industry had "turned" on her.
"This thing that was my best friend for a long time suddenly turned on me," Heigl told the publication in 2014.
"And I didn't expect it. I was taken by surprise and angry at it for betraying me.
Again, that didn't go down well.
Many thought she was just throwing a pity party rather than owning up to her mistakes.
It didn't get any better from there, after she featured in the 2015 dark comedy Home Sweet Hell, which was released to video after a brief theatrical run in North America.
She also received another Golden Raspberry Award nomination for Worst Actress.
Trying her luck back on the TV screen, Heigl signed on for the NBC drama series State of Affairs, which aired in 2015 to bad reviews and was cancelled after one season.
In 2017, Heigl replaced KaDee Strickland in the lead role of Sadie Ellis, in the CBS legal drama Doubt, which was cancelled after only two episodes.
Heigl finally apologised for her Grey's snub in a 2016 interview with Howard Stern, admitting she was "embarrassed" and actually approached Rhimes after it all went down to say sorry.
"I went in because I was really embarrassed. So I went in to Shonda and said, 'I'm so sorry. That wasn't cool, I should not have said that'," she said.
"And I shouldn't have said anything publicly. But at the time, I didn't think anybody would notice. I just quietly didn't submit and then it became a story, and I felt I was obligated to make my statement."
Heigl, who has three children with her long-term husband, singer Josh Kelly, was thrown a lifeline last year by none other than Meghan Markle, the now Duchess of Sussex.
After Markle left the USA Network drama Suits to marry Prince Harry, Heigl was cast as her replacement in a move dubbed her "TV comeback", given the show's massive following. The final season is now streaming on Foxtel.
"Joining Suits was the perfect organic way to not only collaborate with an E.P. I admire deeply, but to also become part of a show and cast that I am an immense fan of," Heigl told T.H.R.
"I have watched Suits from the very beginning and feel incredibly lucky to be the newest member of the Pearson Specter Litt family."
Most recently, Heigl has begun filming Firefly Lane, a Netflix series based on the novel by Kristin Hannah.
She debuted a brand new brunette hairstyle for the role of Tully Heart in a selfie uploaded onto her Instagram account this week.
It has been a rough few years for the star, but it seems she might finally be finding her way back in Hollywood's good books.