Okay, so.
Yes, when you're planning on running a Cortex game, you're not really thinking of running any Cortex game. You're either thinking of running one of the pre-published implementations-- I cut my teeth on Marvel Heroic Roleplaying, but I've played... one of the Firefly games... and a few other umpires' custom builds-- or you're planning on building one of your own, and assembling the system is just like assembling the setting for a homebrew D&D game. The decision points are different, but they're not really different in kind or even in number; you just have to embrace these decisions as something that other games make for you, and you're going to have to make for yourself... even if you just follow another game's template, like I usually do.
The biggest decision, both in difficulty and in importance, is deciding what Trait Sets are going to be used in your game-- this is where you telegraph to your players what's important in the game, and these trait sets are going to do almost all of the mechanical heavy lifting in the game itself. I got started with MHR, which uses Distinctions (free-form descriptors), Affiliations (whether you're currently working on your own, with a partner, or with a team), one or two Power Sets, and Specialties. Mostly. All of these Trait Sets use the same d4-d12 scale. In vanilla MHR, Affiliations is important because they reflect character traits-- Spider-Man teams up with everyone but isn't a team player; Danny and Luke work best back-to-back; Captain America can knock over a HYDRA base with a Little League team-- and are also an unspoken balancing factor, with more godlike characters being devastating alone and fading into the background in an ensemble cast.
In Leverage, the core traits are Distinctions (always, just assume this) and... I forget the names, but they basically use D&D ability scores plus the heist role names from the show's introduction (Hitter, Hacker, Grifter, Thief, Mastermind) and... I don't have the books on-hand, but 3-4 sets is pretty standard. This emphasizes what you do, and how you do it, and importantly every character On the Job has some capacity in every role.
Now, I got started with MHR but... I pretty immediately wanted to start using it for games based on Marvel's eXiles comics from the turn of the century. It's a good setup for MHR with strangers, because every character is a cross between a canon character and an OC and you can turn pretty much any random wiki crawl into useful content. But it is a lot more difficult to use the Affiliation set meaningfully and... it always relies on some contrivance from the Watcher for maximum results, and everyone just has to buy into it, but the eXiles setup means it's almost always pure contrivance and it wears thin.
But as a game that throws people together from different universes and doesn't particularly respect their motivations or ethical frameworks? In a game that could have a team of cyberpunk vampire Captain America, Frank Castle the God Butcher, Doctor Octopus, and Wilson Fisk as the Iron Fist... a game like that gets a lot of mileage out of defining the characters' driving passions and their beliefs about the multiverse. Some dear friends who've played in my games before designed an MHR variant for their games that replaces Affiliations with Values (safety, glory, home, justice, violence, freedom) and freeform Statements that enhance rolls for adhering to them... and provide character growth for challenging them.
They also added Relationship Dice, which are consumable d6s assigned at the start of every Mission to a list of characters (including the other PCs) that reflect their personal connections with the versions of those characters from other timelines. It's a nice bit of foreshadowing for the Mission itself, and encourages players to come up with-- and disclose-- details about their characters' origins organically.
One of my favorite moves, as the sinister umpire that I am, is to throw a fairly standard Frank Castle into a Mission and encourage the players to trade their Punisher War Stories. A couple of Missions later, if the game goes that well... they get the Mission to stop Frank Castle the God Butcher from exterminating... Asgard.
The most stereotypical D&D build would probably look similar to Distinctions (always), Abilities (Sacred Six), the 4e notions of Role and Power Source, and Background/Theme with more detailed character stuff being SFX. Like a Fighter's cleave attack might allow them to roll an extra d6 per extra enemy they want to attack, and keep an extra effect (damage) die to damage them. (Which is a small increase to their chance to hit, a major boost to AOE damage, but increases their chances that something goes wrong.) A Paladin's divine smite might allow them to spend a resource of some kind (usually a Plot Point, but why not introduce D&D-style resources?) to add their Charisma (or Divine) die to a melee attack, keep an extra die for a status effect, and step both dice up by +1.
I mentioned that I prefer Cortex even to AD&D for running Planescape games.
All of the standard D&D trait sets are going to get weird and squishy when applied to The Multiverse and we need to make room for that sweet PS theme stuff. So we are going to take Abilities and Role and Power Source and we're going to combine them all. Warrior, Rogue, Envoy, Mage, Priest and Mystic if you feel like it. There's a deliberately a lot of overlap there, and you can always use the better die.
And then (blasphemy) we are going to combine our Distinctions with our Beliefs. These are player-selected, ranked from d6/d8/d10 (to start); one of them (optionally) is tagged as your Faction belief, and you can tag one for your divine patron, and up to two for your (sub)race/bloodline whatever. If what you're trying to do aligns with one of your Beliefs, you can roll the die for it; if it pretty directly contradictions one of your Beliefs you can triple that Belief die... but then you either have to revise the Belief, or lower it. This process fuels the Growth Pool you use to increase your other dice.
I'm a huge fan of Barbarians of Lemuria, and I keep trying to make a Cortex hack-- Abilities, (Non)combat Techniques, and Careers, with room for some kind of special sauce. Like some kind of fantasy martial arts.
My wife ran her first campaign (ever) last year, a locked-room murder mystery on the first intercontinental dirigible flight. The trait sets were Class (first/economy/steerage/officers/crew) and... actually I don't remember the others. The characters were an American industrialist (me) trying to "solve" the murder first to control the Big Reveal, the manager of the housekeeping staff trying to destroy the airline, and a charlatan just trying to get away with a different murder with his ballerina lover.
