There are many reasons to love Grey’s Anatomy. The compulsively watchable show features impossibly quotable dialogue, epic romances and insane medical cases set to an awesome soundtrack. Currently wrapping up its 15th season, the series was recently renewed for two more, so fans won’t have to say goodbye any time soon.

One of the defining characteristics of Grey’s Anatomy has become its revolving cast of characters. The doctors that populated Seattle Grace in the pilot are now almost completely different, with very few mainstays. Even the name of the hospital has changed. Anyone who’s stuck with the series will tell you that it has viewers regularly reaching for their hankies. Over the years, fans have said goodbye to plenty of beloved characters. Here are the 10 that hurt the most. Side note: how does Grey Sloan Memorial continue to keep hiring doctors when the hospital has such a high mortality rate for employees?

Samuel Norbert Avery

Viewers rejoiced when April Kepner and Jackson Avery finally got together - sorry Matthew. When the fan favorite couple realized that they were going to have a baby, both were overjoyed. However, that excitement was soon decimated by the reality that their child’s poor health wouldn’t see him survive outside the womb.

Due to April’s religious beliefs, she refused to terminate the pregnancy, a decision that she and Jackson clashed over. In the end, April gave birth to the child that they named Samuel Norbert Avery. His parents held him for several agonizing moments until he died. Jackson and April did eventually have another baby, but their relationship never recovered from the loss of Samuel.

Ellis Grey

Ellis Grey (Kate Burton) was never a great mom. A fantastic surgeon, sure, but she was never going to win Mother of the Year. Much of Meredith’s “dark and twisty” personality could be attributed to her upbringing. In fact, Ellis was such an unlikable character that her death on its own might not have been so heartbreaking, if not for the effect that it had on Meredith.

After Ellis was diagnosed with early onset Alzheimer’s disease, Meredith became her primary caretaker, as well as the sole keeper of her secret. After a distressing conversation that almost made Meredith decide to give up on life altogether, mother and daughter finally had a nice chat…in Meredith’s subconscious. She eventually returned to the land of the living, but Ellis was gone for good.

Henry Burton

Before Scott Foley was bashing skulls on Scandal, he was stealing hearts on Grey’s Anatomy. As Henry Burton, Foley not only charmed audiences, but Dr. Teddy Altman as well. In fact, Teddy was so taken with him that she offered to marry the heart patient so that he could use her health insurance, granting him the medical care that he so desperately needed. Despite the contrived way in which their marriage began, as well as Teddy’s various attempts not to fall for him, they eventually became a real couple.

This is Grey’s though, so soon after, Henry was rushed into surgery. It was performed by Cristina, but the identity of the patient was purposely kept from her in the hopes that she could save him. She was unsuccessful and Henry died, breaking viewers’ hearts right along with Teddy’s.

Adele Webber

Poor Richard Webber. To have not one, but two women that you love suffer from Alzheimer’s disease, is a cruel twist of fate indeed. After watching Ellis slip away, Richard was forced to do the same with his wife, Adele (Loretta Divine). From the crushing realization that he could no longer care for her to the revelation that she’d fallen for someone else and no longer recognized him, her battle with the disease was brutal.

Adele eventually passed from a heart attack. Even after her death, Richard still showed up to Bailey’s wedding, despite his clearly broken heart. It was one of the most soul-crushing moments in Grey’s history.

Lexie Grey

Grey’s Anatomy is known for its brutal season finales and although season 6 wins in pure carnage, few episodes have had more long-lasting ramifications than the plane crash that capped season 8. Lexie Grey (Chyler Leigh) had become a fan favorite by that point and no one saw her death coming. The image of her slipping away while trapped under the wreckage as Mark holds her hand is one of the show’s most painful scenes.

Compounding the issue was Lexie and Mark reaffirming their love for one another - the fan favorite couple had been broken up for quite some time. In typical Grey’s fashion, the audience got the reunion that they’d been waiting for, but only so writers could further twist the knife.

Mark Sloan

Speaking of the devastating plane crash and the writers’ penchant for twisting the knife, Mark Sloan (Eric Dane) made it back to Seattle, but only so that he could die there. Apparently, when it was decided that Sloan was to be written out of the show, sending him to LA to live happily ever after with Addison over on Private Practice was briefly considered. However, the idea was scrapped due to Mark’s grief over Lexie’s death, as well as the fact that he’d never leave his daughter, especially in light of Arizona’s injuries.

The most painful part of saying goodby to McSteamy was that Grey’s made us say it twice. Fans were forced to watch the excruciating scene of his friends choosing to withdraw care - per his wishes. However, the very next episode featured flashbacks revealing that he was awake for a while before slipping into a coma.

George O’Malley

While it is true that the tragic death of George O’Malley (T.R. Knight) would’ve had more impact if he’d spent a bit more time on screen in season 5, it was still incredibly upsetting. Of course, he went out like the hero that fans always knew he was, literally jumping in front of a bus to save a stranger’s life. By the time he was rushed to the hospital, George was completely unrecognizable.

It was nice to see him share a final moment with Izzie somewhere between life and death, sporting his new uniform. Still, he was one of the original interns, although hardly any of them are left by this point. He was the first to go and it was painful to witness.

Doc

Doc was Meredith’s dog during season 2. He’s the reason that she met handsome vet Finn Dandridge, but the canine companion also became an unexpected link to Derek after Mer had to re-home him with McDreamy.

Sadly, Doc wasn’t long for this world. Finn diagnosed him with bone cancer and the only real option was euthanasia. Derek and Meredith were both with him in the end, not only grieving Doc, but also the love that they still felt so strongly for one another. If this death didn’t make you cry, it’s entirely possible that you don’t have a heart at all.

Denny Duquette Jr.

When asked about their favorite Grey’s patients, almost everyone will cite Denny Duquette Jr. Jefferey Dean Morgan brought his undeniable charms to the role, once again raising the question of why every TV show and movie seems determined to kill off the characters that he plays. No matter how wrong viewers knew the romance between Izzie and Denny was, it was impossible not to root for them.

Few moments in the series were as gut-wrenching as Izzie showing up in a literal prom dress only to discover that despite all her insane efforts to save his life, Denny was gone. As much as it hurt to watch his demise, most fans would’ve preferred he stayed dead, rather than his strange season 5 return as a ghost/hallucination.

Derek Shepherd

Unequivocally the love of Meredith Grey’s life, there will never be another Der and Mer no matter how hard Grey’s Anatomy tries to create one. The romance between Meredith and Derek Shepherd (Patrick Dempsey) was one of the relationships that made the early seasons of the series so compulsively watchable. Their will-they-or-won’t-they dynamic had viewers hooked from the start and introducing Derek’s surprise spouse did little to derail that faith.

As truly heartbreaking as it was to watch Derek’s death - which was basically the result of medical incompetence - there really was no other way to write him out of the show and still remain true to the epic love story that Shonda Rhimes had been telling for over a decade. McDreamy is still very much missed by both Meredith and fans.