The 10 Most Unmissable Grey’s Anatomy Episodes That Define the Entire Series

ABC’s Grey’s Anatomy being around for more than two decades can make the task of catching up on everything that happened daunting, but watching these 10 episodes helps gain an understanding of what’s at the heart of Shonda Rhimes’ medical drama. With its story developing over 448 episodes and renewed for a 22nd season, Grey’s Anatomy had its doctors come and go and face multiple disasters. Grey’s Anatomy season 21’s ending proved the medical drama has no intention of stopping to put its doctors in unbelievable situations, but some crises were much more crucial to Grey’s Anatomy’s story than others.

With only two original cast members still series regulars and another returning regularly but not anymore part of the main story, Grey’s Anatomy has changed greatly in the past 20 years. The twists and turns, along with the drama-filled romances that made Grey’s Anatomy iconic persisted, albeit inevitably proving more unforgettable in the medical drama’s earlier seasons. With so many changes and so many episodes, it’s easy to lose track of its most important developments, but some episodes exceptionally embody what Grey’s Anatomy has always been about and include some of the twists that affect Grey’s Anatomy‘s story the most.

10A Hard Day’s Night

Grey’s Anatomy Season 1, Episode 1

Grey’s Anatomy’s first episode is necessary, as it brilliantly sets up the medical drama’s key characters, their dynamics, and introduces the most important relationships that will be the focus for many seasons. From Webber and Bailey’s iconic speeches to the interns, to the unexpected reveal of Meredith’s mother’s early-onset Alzheimer’s, everything that happens in Grey’s Anatomy’s series premiere matters for the show’s overall story.

“A Hard Day’s Night” kickstarts Meredith and Derek’s romance with their meet-cute and the inescapable problem of Derek being Meredith’s superior. Grey’s Anatomy season 1, episode 1 also introduces the alliance between Meredith and Cristina that will become the most unique friendship, along with hinting at Meredith and Richard’s complicated relationship. It’s impossible to fully grasp what happens later in Grey’s Anatomy without its pilot episode.

9Losing My Religion

Grey’s Anatomy Season 2, Episode 27

A few key things happen in Grey’s Anatomy season 2’s finale, with Richard’s niece’s prom dance at Seattle Grace offering the perfect bittersweet setting. “Losing My Religion” focuses on the investigation over the cutting of Denny’s LVAD wire, but it also has Meredith and Derek going through euthanizing Doc, and the aftermath of Burke’s surgery.

“Losing My Religion” establishes that any character is fair game, and it also delves beautifully into all its protagonists’ character development.

Grey’s Anatomy season 2, episode 27 is nevertheless synonymous with Denny’s death, with its happening after the successful surgery making everything more heartbreaking. Izzie is left destroyed by Denny’s death, which is also the first major one in the medical drama, making the entire episode necessary to understand Izzie’s storyline the following season, but also Meredith and Derek’s and Cristina and Burke’s. “Losing My Religion” establishes that any character is fair game, and it also delves beautifully into all its protagonists’ character development, making it a key episode to watch.

8Some Kind Of Miracle

Grey’s Anatomy Season 3, Episode 17

Grey’s Anatomy season 3, episode 17 is the last of the three-episode arc covering the ferryboat incident and Meredith almost drowning. “Some Kind of Miracle” has Meredith finally in the hospital, between life and death as Richard, Burke and Bailey try to revive her. It’s the first episode to establish Grey’s Anatomy’s afterlife limbo, which will also return for other characters.

Derek is particularly negatively affected by Meredith’s condition, as he thinks she may have chosen not to fight for her life when in the water, knowing she could swim.

Grey’s Anatomy season 3, episode 17 is also the episode when Ellis Grey dies, but Meredith is saved and decides she wants to live. All the original interns are affected in different ways by Meredith being between life and death, but Cristina is obviously the one most rattled. “Some Kind of Miracle” is essential for season 3’s later storylines, but also in the conclusion of Ellis and Meredith’s complicated bond.

7Now Or Never

Grey’s Anatomy Season 5, Episode 24

Grey’s Anatomy season 5’s finale is also among the unmissable ones in the medical drama. Between Seattle Grace coming to terms with George choosing to enlist and their stress not knowing where he is, the doctors are also forced to deal with Izzie’s tumor after her surgery. However, what makes “Now or Never” one of the most shocking Grey’s Anatomy episodes is the incredible revelation that O’Malley was actually the John Doe who saved a stranger from an oncoming bus.

Grey’s Anatomy season 5’s finale raised the stakes, putting two central characters in danger and killing off one of them after his exit was already sorted out. Grey’s Anatomy isn’t the same after George’s death, with “Now or Never” fully establishing that the worst could happen to anyone at Seattle Grace, even to one of its most beloved residents.

6Sanctuary & Death And All His Friends

Grey’s Anatomy Season 6, Episodes 23 & 24

The two-part finale of Grey’s Anatomy season 6 is among the deadliest, starting out with the unexpected killing of Reed, only to continue adding to the episode’s victims’ ranks as Gary Clarke meets doctors unwilling to help him exact his revenge. Grey’s Anatomy peaked with “Sanctuary” and “Death and All His Friends,” thanks to its threats to key characters like Derek, Owen and Alex, while also putting Cristina and Meredith in impossible situations.

All episodes of Grey’s Anatomy season 21 will be available to stream on Netflix from 3am ET on Saturday, June 14, 2025.

How the disaster could have easily taken any of Grey’s Anatomy’s protagonists’ lives makes this crisis one of the medical drama’s most effective. Its prompting character development, changing the lives of so many, and generally being so impactful that Grey’s Anatomy season 6’s finale’s storylines influence so much of season 7 make it impossible to miss it.

5Flight

Grey’s Anatomy Season 8, Episode 24

Similar to season 6’s finale, the final episode of Grey’s Anatomy season 8 should also not be skipped. The episode leaves who will become the Seattle Grace Five in terrible circumstances, forgotten by the world in the midst of a crashing site, fending for themselves and the bodies of their friends.

“Flight” emotionally rips Lexie from Meredith, and all-in-all establishes storylines that will be important years from that moment in Grey’s Anatomy. Lexie’s death, Arizona and Derek’s severe wounds can be difficult to watch, but they make Grey’s Anatomy season 8’s finale its most traumatic episode to date.

4Get Up, Stand Up

Grey’s Anatomy Season 10, Episode 12

Unexpected among so many season premieres and finales, Grey’s Anatomy season 10, episode 12 is unmissable because it entails Japril finally becoming an item after Jackson effectively crashes April’s wedding and April leaves Matthew at the altar. The episode also sets up the reason for Meredith and Derek’s major fights throughout season 11, and it concludes Meredith and Cristina’s fights at last, with the two friends facing their choice of different life paths that won’t stop them from making time for one another.

“Get Up, Stand Up” is simultaneously a nod to Sloan through Jackson finally telling April about his feelings and a turning point for Meredith and Derek’s changing relationship. Grey’s Anatomy season 10, episode 12 cannot be missed both for its high level of drama and because it sets up Cristina’s difficult but necessary goodbyes and the most important change for MerDer.

3How To Save A Life

Grey’s Anatomy Season 11, Episode 21

The last episode where Patrick Dempsey appears as a series regular, Grey’s Anatomy season 11, episode 21 is heartbreaking and the perfect hero send-off for Derek. Knowing MerDer’s importance to the story and about Dempsey’s exit from Grey’s Anatomy makes it easy to imagine Derek will have to die to preserve one of the tenets of the medical drama.

[Derek’s] realization of how the local hospital was botching his case after arriving at their ER is heartbreaking, along with Meredith’s goodbyes to him.

Derek saving everyone before succumbing to his injuries makes his last day alive a worthy ending to his story. Still, his realization of how the local hospital was botching his case after arriving at their ER is heartbreaking, along with Meredith’s goodbyes to him. “How to Save a Life” needs to be watched as it’s influential for Derek, always central to Grey’s Anatomy, but also for all the key characters in the medical drama.

21-800-799-7233

Grey’s Anatomy Season 14, Episode 9

Jo Wilson’s abuser appearing at Grey Sloan Memorial makes Grey’s Anatomy season 14, episode 9 one of the most pivotal in the medical drama’s latest seasons. The focus on the important theme makes the episode unmissable because it shows how Paul manipulated everything Jo ever said.

Grey’s Anatomy is available to stream in its entirety on Hulu.

Simultaneously, the episode is also a watershed because it can free Jo from her past at last. Grey’s Anatomy season 14, episode 9 is enormously important for Jo, Meredith and Alex, and its tackling domestic violence so tactfully makes it a must-see, a reminder of Grey’s Anatomy’s typical focus on sensitive themes.

1My Shot

Grey’s Anatomy Season 16, Episode 8

Grey’s Anatomy season 16, episode 8 sees Meredith fight for her medical license after she committed insurance fraud operating on a child whose difficult journey convinced Meredith to make a stand by treating her. The episode acts as a trip down memory lane of everything good Meredith did as a doctor, as well as all the multiple times she broke rules, whether to help friends or because she believed they were wrong.

“My Shot” delivers an emotional recap of Meredith’s most important cases and moments in life, including Derek’s death, with one of the doctors on the panel being the one whose actions killed Derek. Meredith saving him despite their history proves everything there is to know about her, with Grey’s Anatomy season 16, episode 8 beautifully paying tribute to Meredith and her progress in the best way.