Depends on the edition.
Haven't touched it since the 1980s. Probably wouldn't run it, since all that would remain is my hacks.
Eliminate racial level caps. Change THACO/AC to the 3e system. Encourage specialty clerics. Mandate weapon/nonweapon proficiencies.
Ignore "favored class" as a concept. If humans complain, toss them an extra Feat every now and then. Revise list of cross-class skills for concepts that don't fit existing character classes. Otherwise undermine the idea of character classes whenever possible. Estimate, don't calculate, the various fiddly bonus types. Improvise Grapple, Jump, and Attacks Of Opportunity as needed.
Don't play it. If forced to, use the class-free 4.18 ruleset I patched together. Eliminate all powers that require a grid/battlemat; replace them with freeform powers. Add powers that work outside of combat.
Marvel Super Heroes
Remove the Kill result from Energy attacks and replace it with Stun. Reduce the Karma cost for doing a Power Stunt the first time.
Scrap their systems for initiative and damage. Replace the former with a simple everyone-takes-a-turn rotation. Replace the latter with an impressionistic system where damage rolls are compared to Strength rolls and the result means the target is stunned/wounded (if a PC) or wounded/KO'd (if an NPC), based on how entertaining the fight has been so far. To improve one of your stats, raise at least 5 of its Skills by one level. Pretend that the d20 version never happened. Pretend that anything written by Bill Slavicsek never happened.
Ignore the various hard-coded environmental modifiers. Ignore the rules for accelerating, decelerating, and gaining altitude with Flight (unless someone who took Gliding really wants to feel special). Allow someone to have a Base with a Vehicle with a Follower, provided that they're Having Fun With The Rules instead of Being A Stupid Munchkin.
Call of Cthulhu
Can't think of a thing.
Eliminate the Roles. Let players pick the skills they want. Allow players to take a second Role-based skill, provided it doesn't start at more than half the level of the first Role skill. Skip the dumb parts of the Lifepath, where you can end up a barenaked corporate mogul living on a pirate raft... wait, that's awesome. But let people who don't see the awesomeness skip those parts of the Lifepath.
Discard 95% of the setting's politics, geography, and ongoing plots. Replace with actual 17th century Eurasiafrica, with an option on the Americas. Discourage players from taking Backgrounds if they're the kind of people who don't like having their character's history become the party's plotline. The Advantage called Faith does nothing.