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An actor who nailed a role so HARD that nobody else will ever be able to live up to it

Reese Witherspoon - Legally Blonde. This is the movie I really respected her acting ability.

Marissa Tomei - My Cousin Vinny. She wears this role as a suit. Pesci is the star, but this movie sucks without Tomei. She doesn't look for a second to be acting, you'd swear that was just some New York girl straight out of a stereotype description.

Christian Bale - American Hustle. Not acting, being.

Peter Sellers - Every role he has ever played. You can't redo Peter Sellers.

James Earl Jones - Great White Hope. Historically, the film is a sham. But as a reproduction of the Broadway Stage show, OMFG, he kills it in this role. You can't remake it.

Jack Lemmon - Save the Tiger, The Apartment, The Wackiest Ship in the Navy.

Patrick Stewart - Dr. Freeze... oh wait, they messed that one up.

Daniel Day Lewis - Any role he has had. Hollywood fears making films with him because they have to retire the movie after he stars in it.
 
Jack Lemmon - Save the Tiger, The Apartment, The Wackiest Ship in the Navy.
Also, he just kills it in Glengarry Glen Ross as the washed-up senior salesman. By the middle of the film you know everything there is to know about this oily conman. And in his final scene, he comes apart and stands revealed as a devastated old man. It's painful to watch.
 
Great topic but there are just too many answers! My list is weighted toward the films of 50+ years ago. Here are performances I keep coming back to, sometimes just to hear how a key line is given the most powerful possible reading:

Charles Laughton, in Witness for the Prosecution (Key line: "LIAR!!!")
Garbo in Ninotchka (if champagne was a woman...)
Ben Johnson in The Last Picture Show
Cloris Leachman, The Last Picture Show (steals the picture in her final scene)
Meryl Streep: you name it
Thelma Ritter: ditto
Dustin Hoffman, Tootsie
Bogart in The Maltese Falcon and The Treasure of the Sierra Madre (he was not Oscar-nommed for either role!)
Al Pacino, Glengarry Glen Ross
Olivia Colman, The Favourite
Olivia de Havilland, The Heiress (not a false moment in this performance)
Phillip Seymour Hoffman -- every role, but especially as Freddie in Ripley and as the title role in Capote
 
Malcolm McDowell - A Clockwork Orange.

Humphrey Bogart - Casablanca. But then the same can be said for Ingrid Bergman, Paul Henreid, and Claude Rains in the same film as well.
 
Great topic but there are just too many answers! My list is weighted toward the films of 50+ years ago. Here are performances I keep coming back to, sometimes just to hear how a key line is given the most powerful possible reading:

Charles Laughton, in Witness for the Prosecution (Key line: "LIAR!!!")
Laughton, I forgot about him. One of the best movies ever made. Laughton had a tendency of being big on screen very often. But his role, heck, everyone in this film is great. His role in Mutiny on the Bounty was very good as well.
Dustin Hoffman, Tootsie
Hero would be better.

Bette Davis effectively playing herself in All About Eve.

Walter Matthau The Front Page
 
Alec Guinness in almost anything he appeared in. I'll just mention "Bridge on the River Kwai" and for comedies, I was always partial to "The Horses Mouth," although all his comedies from the '50s and '60s are genius.
 
Geoffrey Rush is another actor whose work I find to be miraculous. He's only fitfully active these days (there were sexual harassment allegations in the late teens, and he withdrew from film projects.) I haven't been able to see all of his most celebrated titles, but what I've seen ranks him with the best American talents. I wish he'd been able to work with Philip Seymour Hoffman, and I wish he would still find a project to do with Meryl Streep. Among the indelible Rush performances: The King's Speech, where he is subdued, civilized, sympathetic; Quill, the opposite end, where he plays DeSade; The Life and Death of Peter Sellers (simply incredible, he becomes Sellers.) He's the only reason I would rewatch Intolerable Cruelty.
 
The first Godfather cast.

Al Pacino
Marlon Brando
James Caan
John Cazale

It may not qualify because there were sequels though, so I'll mention Jack Nicholson in The Shining. Between Kubrick's directing and Nicholson's acting, both the movie and the role is broken forever.
 
Gregory Peck in To Kill a Mockingbird.
James Stewart in Harvey
Grace Kelly in any Hitchcock film.
Burt Lancaster in Field of Dreams, Atlantic City and Bird Man of Alcatraz
Cary Grant in Charade, North by Northwest and My Favorite Wife
Eva Marie Saint, James Mason and Martin Landau in North by Northwest
William Powell and Myrna Loy in The Thin Man
 
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Groucho Marx, in any role he did. He was truly one of a kind. He may not have been a 'great' actor, but I can't imagine anyone out doing him at what he did.
 
Kevin Kline in A Fish Named Wanda. I find this performance to be under appreciated. I find Kline in general, is under-rated as a comedy actor.

Spencer Tracy and Katherine Hepburn in Adam's Rib. You can remake this, but the connection between these two on screen (in real life) would be impossible to recreate.

Groucho Marx, in any role he did. He was truly one of a kind. He may not have been a 'great' actor, but I can't imagine anyone out doing him at what he did.
In my opinion, that was more of a team thing. It can't be replaced, not because it was hammered, but rather because they did it first and it belongs in its own time.
 
Gregory Peck in To Kill a Mockingbird.
James Stewart in Harvey
Grace Kelly in any Hitchcock film.
Burt Lancaster in Field of Dreams, Atlantic City and Bird Man of Alcatraz
Cary Grant in Charade, North by Northwest and My Favorite Wife
Eva Marie Saint, James Mason and Martin Landau in North by Northwest
William Powell and Myrna Loy in The Thin Man
I’ll add Lancaster’s role in Seven Days in May.
 
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