Caine's breakthrough as a leading man came early with the epic film Zulu (1964), which he immediately followed with this adaptation of Len Deighton's espionage novel. This was the first of his several appearances as Harry Palmer, a working-class spy whose life is endangered when he becomes entangled in an international conspiracy. Director Sidney J. Furie startled audiences with his stylized camera choices and the presentation of Caine's anti-007, complete with signature thick-rimmed eyeglasses.

Caine would reprise the role on the big screen in Funeral in Berlin (1966) and in Billion Dollar Brain (1967), as well as in two made-for-TV '90s entries.

Caine earned his first Oscar nomination for Best Actor in a Leading Role (and got his most famous movie theme song, "Alfie," penned by Burt Bacharach and Hal David) with this wildly popular and slightly naughty comedy-drama. Here, Caine plays the title character, a woman-crazy, narcissistic chauffeur who occasionally breaks the fourth wall and speaks directly to the audience. The popularity of Alfie was instrumental in sparking a Swinging London craze across the moviegoing world for the rest of the decade. In addition to the Oscar nomination for Caine's performance, Alfie was also nominated for Best Picture, Best Adapted Screenplay, Best Actress in a Supporting Role for Vivien Merchant, and Best Original Song for the previously mentioned song "Alfie."

Directed by Mike Hodges, the British gangster drama, Get Carter, tells a tale of revenge. Caine plays Jack Carter, a tough London gangster, whose brother winds up dead. Although his brother died in a car accident, Jack Carter is convinced that his brother was murdered. He travels to Newcastle to look into matters, and his quest ultimately leads him to the local kingpin. Caine's deliberately ice-cold performance as Jack Carter has been regarded as iconic in the years since the film's release.

In 2000, the film was remade with Sylvester Stallone playing Jack Carter. Caine is actually in the remake, as well, this time playing the former employer of Carter's deceased brother.

A smash Tony-winning suspense play by Anthony Shaffer became an influential screen classic with the pairing of Caine and Sir Laurence Olivier (both nominated for the Best Actor in a Leading Role Oscar) at a remote estate in the English countryside. Openly cited as an influence on Knives Out (2019), the story pits Olivier’s arrogant, cuckolded mystery writer in a battle of wits with Caine's upstart rogue who’s been seeing the scribe's wife behind his back. Murder ensues… or does it? Caine would mine similar territory in Sidney Lumet's adaptation of Ira Levin's hit play Deathtrap (1982).

In 2007, he reprised Sleuth by taking on Olivier's role in Kenneth Branagh's film version adapted by Harold Pinter, with Jude Law, who also played Alfie in the 2004 remake of Alfie, playing the role Caine played in the original Sleuth.

Caine took on the most unexpected role of his career in writer-director Brian De Palma's twisty, stylish thriller where New York City turns into a maze of lust and murder. Caine plays the upscale psychiatrist whose client, frustrated housewife Kate (Angie Dickinson), initiates a shocking mystery involving an unstable patient with a straight razor. Caine plays a pivotal role in the audacious final act. Initially controversial, the film has since gone on to be regarded as one of De Palma's most inventive and flamboyant achievements.

Caine earned his third Oscar nomination and teamed up again with his Alfie director, Lewis Gilbert, for this surprise hit comedy-drama. In her first film role, future Harry Potter and Mamma Mia! actress Julie Walters (who had appeared in the stage version and also received an Oscar nomination for her leading performance) plays a hairdresser who forms an unlikely bond with Caine's alcoholic professor teaching her college literature class. The engaging pairing of the lead actors marked a turning point in Caine's career, leading to several acclaimed international productions throughout the decade and a new level of acclaim from critics and audiences. 

A comedy classic was born when Caine, now an Oscar winner for Best Actor in a Supporting Role for Hannah and Her Sisters (1986), and Steve Martin joined forces as a pair of rival con artists who begrudgingly team up for an escalating series of marks on the Riviera. Directed by Frank Oz, the film takes inspiration from the 1964 comedy Bedtime Story and replaces its romance angle with a berserk series of plot twists involving the men's attempts to con a young American heiress (Glenne Headly). The film went on to inspire a successful Broadway musical in the mid-2000s and a gender-swap remake, The Hustle (2019), starring Rebel Wilson and Anne Hathaway.

Viewers were surprised when Caine portrayed what may be the screen's most soulful interpretation of Ebenezer Scrooge in this Muppet-fied take on the perennial yuletide classic by Charles Dickens. Caine deliberately approached the role as a purely dramatic one among the Muppet characters, with extensive visual wizardry placing them all in 1840s London in December. The film has since become a holiday classic and can be seen in an extended cut featuring a song that's key to Scrooge's past.

Caine won his second Best Actor in a Supporting Role Oscar for Lasse Hallström's emotional dramatization of the beloved book by John Irving, who also won an Oscar for Best Adapted Screenplay. Caine plays Dr. Wilbur Larch, a physician who takes a special interest in one of the orphans he looks after, Homer Wells (Tobey Maguire). His signature line, "Good night, you Princes of Maine! You Kings of New England!," is taken straight from the book and found its ideal voice in Caine's performance.

The same time he appeared as the father of Mike Myers' character in Austin Powers in Goldmember (2002), Caine earned another Oscar nomination for Phillip Noyce's adaptation of Graham Greene's Vietnam-set novel (previously adapted far less faithfully in 1958). Caine appears opposite Brendan Fraser for a look at Western intervention in 1952 Saigon, with Caine's journalist character, Thomas Fowler, narrating how he became involved in CIA meddling that would escalate local tensions and lead to murder.

Caine returned to his Get Carter roots with this tough-as-nails vigilante drama set in a rough housing estate in London. He plays widowed military vet Harry Brown, who is pushed to take action by the escalating crime around him. His experiences in Northern Ireland have honed deadly tactics and he puts them to use. A kind of link between the classic payback films of Charles Bronson and current films like Taken (2008), Harry Brown marked a high point during several substantial roles for him around this time, just after his notable turns in Children of Men (2006), The Prestige (2006), and The Dark Knight (2008), and paving the way for his work in Inception (2010), Now You See Me (2013), and Kingsman: The Secret Service (2015).