The episode "Hulkbuster" saw both Bruce Banner and Hulk being voiced by Ron Perlman.
The Other Darrin: Dorian Harewood took over for James Avery as War Machine, Whirlwind, and Whiplash early into Season 1. Also, Harewood, Robert Hays, John Reilly (the voice of Hawkeye), Jim Cummings and Neil Ross (Fin Fang Foom) were the only cast members to return for Season 2. Virtually everyone else was replaced.
Century also suffered from this... twice! His original voice actor was among those let go in-between seasons. In "The Beast Within," Jim Cummings takes over voicing the character. But in "The Hands of the Mandarin" two-parter, fellow series regular Tom Kane had the role instead. (This was most likely because H.O.M.E.R. didn't appear in Part 2 and production wanted Kane to have something to do.)
Ability Over Appearance: Pepper Potts as played by Gwyneth Paltrow differs quite a way from her comic book counterpart, who starts out in her early-to-mid twenties and is correspondingly immature at times; the original plan for the movie more or less followed this, with Pepper implied to drop out as a potential love interest after the first movie due to her inability to cope with Tony's new lifestyle. Gwyneth Paltrow's Pepper is at least ten years older than her comic book counterpart and is shown to be mature, capable and loyal due to her greater experience and longer stint as Tony's PA; and it's probably no coincidence that she's become one of the most popular secondary characters in the MCU.
Mickey Rourke visited the infamous Butyrka prison in Moscow to study the mannerisms of real-life Russian criminals. Bizarrely enough, Rourke noted the prisoners were actually pretty nice. He also put himself through emotional hell by having the director hold up pictures of his favorite (now passed) pets for scenes where he needed to be anguished or enraged (or both, as so often goes together with him).
Robert Downey Jr. gained muscle to play Tony Stark, though he'd already been quite fit.
Gwyneth Paltrow and Scarlett Johansonn turned into redheads. The latter hadn't even been cast yet, she just wanted the role that bad.
Jeff Bridges actually looked forward to the idea of shaving his head for the role of Stane—he'd been planning on doing it for years, and this was his excuse.
Faran Tahir, the actor who played Raza, trying to avoid the stereotype of the Middle Eastern terrorist and invoke the, for lack of a better term, multiculturalism of the Ten Rings, used more than one language other than English and even varied his accent a little (he's American, but from a Pakistani family).
Robert Downey, Jr.'s dialogue was heavily improvised in all three movies, which was intentional to help make his character seem relatively One of Us, even if he is a Fiction 500 charter member.
In many ways part of the style of directing used in the films, with other instances being the little dance Hammer does at the beginning of his presentation and "too disco".
Writing by the Seat of Your Pants: A script was written, but as the actors continued to come up with lines that better suited the film, halfway through shooting, they just went "To hell with it", threw away the script (which was constantly being rewritten every night), and wrote outlines of the scenes.