Pro: The Big Game is easier to find players for than anything else. People are likely to own or willing to buy the relevant player's books. Lots and lots of support products available. Lots of cool books for the players. Can consider using all sorts of nifty rules, like in the new Unearthed Arcana.
Con: Defaults to bog standard traditional fantasy. My personal handling time for pre-game prep is so large that it discourages me from writing my own materials, limiting the game to largely whatever 3.X modules I can bring to bear.
Pro: No frickin' elves! Great new races and classes that totally replace all the old ones. Nifty magic system. Interesting setting and metaplot. Rules not totally alien to the 3.X folks. Product support from Messrs. Cook and Mearls. Very cool.
Con: No frickin' orcs! Very expensive corebook will discourage other players from buying. Relatively obscure game line, with obscure races and classes.
Castles & Crusades
Pro: Easy as pie for an old schooler to understand. Cheap corebook. All my old stuff is easily adaptable, much of it could be done on the fly. That big epic game would probably be easiest to run with this, though not as flavorful as using AE. Castle Zagyg (Uncle Gary's dungeon) might be available in the forseeable future. Fiddling with the rules seems less intimidating than in the 3.X game.
Con: The classes might seem dull to a d20 wonk. System support is currently a trickle of products.
I can't quite pick a system at this point, but the comparison has helped crystalize 6 possible campaigns in my mind.
Dungeonpunk: The Modulation - 3.5 rules, canned modules
The Dragon War - AE rules and setting, big epic war story
The Crusade - C&C rules, setting undecided at this point, big epic war story
You're All In A Tavern - AE rules and oversetting, small local setting with small local dungeons and small local adventures, in the Grand Duchy of Karameikos style but with AE window dressing
Zagyg Castle & Environs - C&C rules, focus on the Big Dungeon with sidetracks in the surrounding territory
And the Kitchen Sink - C&C rules, adventures and monsters and magic items pulled from all the old stuff in my collection
That last one would no doubt be the easiest to run, but if I could magically guarantee the success of a campaign I would try the Dragon War hands down. With the right setting the 3 C&C options could be folded together, intertwined, or run as a sequence of campaigns. The two AE ideas could be considered as a unit as well, with the age of dungeoneering innocence giving way to an era of brutal draconic war.